Therapeutic pyrazolo[3,4-b]pyridines and indazoles

ABSTRACT

The present invention provides for compounds of Formula I: 
                         
wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, and L have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of central nervous disorders and conditions including attention deficit hyperactivity disorder, neuropathic pain, urinary incontinence, anxiety, depression, and schizophrenia and fibromyalgia. Also provided are pharmaceutical compositions comprising one or more compounds of Formula I.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 11/287,759, filedNov. 28, 2005, now U.S. Pat. No. 7,423,054, and claims the benefit ofU.S. Provisional Patent application Ser. No. 60/631,386, filed on Nov.29, 2004, the teachings of each of which are herein incorporated byreference.

BACKGROUND OF THE INVENTION

The monoamines norepinephrine and serotonin have a variety of effects asneurotransmitters. These monoamines are taken up by neurons after beingreleased into the synaptic cleft. Norepinephrine and serotonin are takenup from the synaptic cleft by their respective norepinephrine andserotonin transporters.

Drugs that inhibit the norepinephrine and serotonin transporters canprolong the effects of norepinephrine and serotonin, respectively, inthe synapse, providing treatment for a number of diseases. For example,the serotonin reuptake inhibitor fluoxetine has been found to be usefulin the treatment of depression and other nervous system disorders. Thenorepinephrine reuptake inhibitor atomoxetine has been approved for thetreatment of attention deficit hyperactivity disorder (ADHD) asSTRATTERA®. In addition, the norepinephrine and serotonin transporterinhibitor milnacipran is being developed for the treatment offibromyalgia, a disease that affects about 2% of the adult population inthe United States. However, the FDA has not currently approved any drugfor the treatment of fibromyalgia. Accordingly, there is an ongoing needin the art for compounds that are norepinephrine transporter inhibitors,serotonin transporter inhibitors, and that inhibit both norepinephrineand serotonin transporters, for the treatment of diseases includingfibromyalgia, ADHD, neuropathic pain, urinary incontinence, generalizedanxiety disorder, depression, and schizophrenia.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides for compounds of formulaI:

or a pharmaceutically acceptable salt thereof; wherein: X is N or C(R⁴);R² is 2-pyridinyl or phenyl, wherein said 2-pyridinyl or said phenyl maybe optionally substituted with one to three substituents independentlyselected from the group consisting of: hydrogen, halo, methyl, ethyl,CF₃, methoxy, CH₂F, CHF₂, and CH₂OH; L is absent or methylene; R³ isselected from the group consisting of: 3-pyrrolidinyl, 4-piperidinyl,3-piperidinyl, and 2-morpholinyl; and R⁴, R⁵, R⁶, and R⁷ are H; or threeof R⁴, R⁵, R⁶, and R⁷ are H and one R⁴, R⁵, R⁶, and R⁷ is selected fromthe group consisting of: halo, methoxy, and a C₁-C₃ alkyl. Examples of aR² phenyl group substituted with one to three substituents independentlyselected from the group consisting of: hydrogen, halo, methyl, ethyl,CF₃, methoxy, CH₂F, CHF₂, and CH₂OH include, but are not limited to,3-chlorophenyl, 2,6-dibromophenyl, 2,4,6-tribromophenyl,2,6-dichlorophenyl, 4-trifluoromethylphenyl, 3-methyl-phenyl,4-methyl-phenyl, 3,5-dimethyl-phenyl, 3,4,5-trimethoxy-phenyl,3,5-dimethoxy-phenyl, 3,4-dimethoxy-phenyl, 3-methoxy-phenyl,4-methoxy-phenyl, 3,5-difluoro-phenyl, 4-chloro-phenyl,3-trifluoromethyl-phenyl, 3,5-dichloro-phenyl,2-methoxy-5-methyl-phenyl, 2-fluoro-5-methyl-phenyl,4-chloro-2-trifluoromethyl-phenyl, and the like.

In certain embodiments of Formula I, X is C(R⁴), R² is phenyl, and R⁴,R⁵, R⁶, and R⁷ are H; or three of R⁴, R⁵, R⁶, and R⁷ are H and one ofR⁴, R⁵, R⁶, and R⁷ is selected from the group consisting of: halo,methoxy, and a C₁-C₃ alkyl.—a compound of Formula II. In certainembodiments of Formula II, R⁴, R⁵, R⁶, and R⁷ are H, and R² isoptionally substituted with one or two substituents independentlyselected from the group consisting of: hydrogen and fluoro. In certainembodiments of Formula II, R³ is a 3-pyrrolidinyl. Examples of compoundsof Formula II where R³ is a 3-pyrrolidinyl include:(R)-1-(2,5-difluoro-phenyl)-3-(pyrrolidin-3-ylmethoxy)-1H-indazole;(R)-1-(2,4-difluoro-phenyl)-3-(pyrrolidin-3-ylmethoxy)-1H-indazole;(S)-1-(2,4-difluoro-phenyl)-3-(pyrrolidin-3-ylmethoxy)-1H-indazole;(S)-(−)-1-(2-fluorophenyl)-3-(pyrrolidin-3-ylmethoxy)-1H-indazole;(S)-1-(2,6-difluoro-phenyl)-3-(pyrrolidin-3-ylmethoxy)-1H-indazole;(R)-1-phenyl-3-(pyrrolidin-3-ylmethoxy)-1H-indazole; and(S)-(−)-1-(2-fluorophenyl)-3-(pyrrolidin-2-yloxy)-1H-indazole. Incertain embodiments of Formula II, R³ is a 3- or 4-piperidinyl. Examplesof compounds of Formula II where R³ is a 3- or 4-piperidinyl includeinclude:(±)-1-(2,5-difluoro-phenyl)-3-(piperidin-3-ylmethoxy)-1H-indazole;1-(3-fluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazole;1-phenyl-3-(piperidin-4-yloxy)-1H-indazole;1-(2,6-difluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazole;1-(2,5-difluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazole; and(±)-1-(3-fluoro-phenyl)-3-(piperidin-3-ylmethoxy)-1H-indazole.Additional compounds of Formula II where R³ is a 3- or 4-piperidinylinclude:(S)-(−)-1-(2-fluorophenyl)-3-(piperidin-3-ylmethoxy)-1H-indazole;(S)-1-(2,6-difluoro-phenyl)-3-(piperidin-3-ylmethoxy)-1H-indazole; and(S)-(−)-1-phenyl-3-(piperidin-3-ylmethoxy)-1H-indazole. In certainembodiments of Formula II, R³ is a 2-morpholinyl. Examples of compoundsof Formula II where R³ is a 2-morpholinyl include:(S)-(+)-1-(2,5-difluorophenyl)-3-(morpholin-2-ylmethoxy)-1H-indazole;(S)-1-(2,6-difluoro-phenyl)-3-(morpholin-2-ylmethoxy)-1H-indazole;(S)-(+)-1-(2,4-difluorophenyl)-3-(morpholin-2-ylmethoxy)-1H-indazole;(S)-1-(3,4-difluoro-phenyl)-3-(morpholin-2-ylmethoxy)-1H-indazole;(S)-(+)-1-(2-fluorophenyl)-3-(morpholin-2-ylmethoxy)-1H-indazole; and(S)-(+)-3-(morpholin-2-ylmethoxy)-1-phenyl-1H-indazole. In certainembodiments, a compound of formula I is(S)-1-(2,6-difluorophenyl)-3-(morpholin-2-ylmethoxy)-1H-indazole, or apharmaceutically acceptable salt thereof.

In certain embodiments, the present invention provides for1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole, or apharmaceutically acceptable salt thereof. In another embodiment, thepresent invention provides for1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-tartrate.

In certain embodiments of Formula I, X is C(R⁴), R² is phenyl, and R⁶ isselected from the group consisting of: halo, methoxy, and a C₁-C₃alkyl—a compound of Formula III. In certain embodiments of Formula III,R² is optionally substituted with one or two substituents independentlyselected from the group consisting of: hydrogen and fluoro. In certainembodiments of Formula III, R³ is a 3-pyrrolidinyl. An example of acompound of Formula III where R³ is a 3-pyrrolidinyl is(R)-1-(2,5-difluoro-phenyl)-5-fluoro-3-(pyrrolidin-3-ylmethoxy)-1H-indazole.In certain embodiments of Formula III, R³ is a 4-piperidinyl or3-piperidinyl. An example of a compounds of Formula III where R³ is a4-piperidinyl or 3-piperidinyl is1-(2,6-difluoro-phenyl)-5-fluoro-3-(piperidin-4-yloxy)-1H-indazole. Incertain embodiments of Formula III, R³ is a 2-morpholinyl. Examples ofcompounds of Formula II where R³ is a 2-morpholinyl include:(S)-1-(2,6-difluoro-phenyl)-5-fluoro-3-(morpholin-2-ylmethoxy)-1H-indazole;(S)-1-(2,5-difluoro-phenyl)-5-fluoro-3-(morpholin-2-ylmethoxy)-1H-indazole;and(S)-(+)-5-fluoro-1-(2-fluorophenyl)-3-(morpholin-2-ylmethoxy)-1H-indazole.In certain embodiments, a compound of formula I is(S)-1-(2,5-difluoro-phenyl)-5-fluoro-3-(morpholin-2-ylmethoxy)-1H-indazole,or a pharmaceutically acceptable salt thereof. In certain embodiments, acompound of formula I is(S)-(+)-1-(2,4-difluorophenyl)-5-fluoro-3-(morpholin-2-ylmethoxy)-1H-indazole,or a pharmaceutically acceptable salt thereof.

In certain embodiments of Formula I, X is C(R⁴), R² is phenyl, and R⁷ isselected from the group consisting of: halo, methoxy, and a C₁-C₃alkyl—a compound of Formula IV. In certain embodiments of Formula IV, R²is optionally substituted with one or two substituents independentlyselected from the group consisting of: hydrogen and fluoro. In certainembodiments of Formula IV, R³ is a 3-pyrrolidinyl. In certainembodiments of Formula IV, R³ is a 3- or 4-piperidinyl. Examples ofcompounds of Formula IV where R³ is a 3- or 4-piperidinyl includeinclude: 4-fluoro-1-(2-fluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazole;1-(2,5-difluoro-phenyl)-4-fluoro-3-(piperidin-4-yloxy)-1H-indazole;1-(2,4-difluoro-phenyl)-4-fluoro-3-(piperidin-4-yloxy)-1H-indazole;(S)-1-(2,5-difluoro-phenyl)-4-fluoro-3-(piperidin-3-ylmethoxy)-1H-indazole;and(S)-4-fluoro-1-(2-fluoro-phenyl)-3-(piperidin-3-ylmethoxy)-1H-indazole.In certain embodiments of Formula IV, R³ is a 2-morpholinyl. An exampleof a compound of Formula IV where R³ is a 2-morpholinyl is(S)-1-(2,5-difluoro-phenyl)-4-fluoro-3-(morpholin-2-ylmethoxy)-1H-indazole.

In certain embodiments of Formula I, X is C(R⁴), R² is phenyl, and R⁵ isselected from the group consisting of: halo, methoxy, and a C₁-C₃alkyl—a compound of Formula V. In certain embodiments of Formula I, X isC(R⁴), R² is phenyl, and R⁴ is selected from the group consisting of:halo, methoxy, and a C₁-C₃ alkyl—a compound of Formula VI. In certainembodiments of Formula I, X is C(R⁴), and R² is 2-pyridinyl—a compoundof Formula VII. In certain embodiments of Formula I, X is N, and R² isphenyl—a compound of Formula VIII. In certain embodiments of Formula I,X is N, and R² is 2-pyridinyl—a compound of Formula IX. In certainembodiments of Formula I, X is C(R⁴), R² is phenyl optionallysubstituted with one or two substituents independently selected from thegroup consisting of: hydrogen and fluoro (e.g., 2,6-difluoro-phenyl,2-fluoro-phenyl, 4-fluoro-phenyl, 2,4-difluoro-phenyl,2,5-difluoro-phenyl, or 3,4-difluoro-phenyl).

In certain embodiments of Formula I, X is C(R⁴), R² is phenyl optionallysubstituted with one or two substituents independently selected from thegroup consisting of: hydrogen and fluoro, and -L-R³ is:

where the wavy line indicates the attachment point to the rest of thecompound.

In certain embodiments of Formula I, X is C(R⁴), R² is phenyl optionallysubstituted with one or two substituents independently selected from thegroup consisting of: hydrogen and fluoro, and -L-R³ is:

where the wavy line indicates the attachment point to the rest of thecompound.

In certain embodiments of Formula I, X is C(R⁴), R² is phenyl optionallysubstituted with one or two substituents independently selected from thegroup consisting of: hydrogen and fluoro, and -L-R³ is:

where the wavy line indicates the attachment point to the rest of thecompound. In certain embodiments, -L-R³ is

where the wavy line indicates the attachment point to the rest of thecompound.

In certain embodiments of Formula I, X is C(R⁴), R² is phenyl optionallysubstituted with one or two substituents independently selected from thegroup consisting of: hydrogen and fluoro, and -L-R³ is:

where the wavy line indicates the attachment point to the rest of thecompound.

In another aspect, the present invention provides for compounds offormula XI:

or a pharmaceutically acceptable salt thereof; wherein: X is N or C(R⁴);R² is 2-pyridinyl or phenyl, wherein said 2-pyridinyl or said phenyl maybe optionally substituted with one to three substituents independentlyselected from the group consisting of: hydrogen, halo, methyl, ethyl,CF₃, methoxy, CH₂F, CHF₂, and CH₂OH; L is absent or methylene; R⁴, R⁵,R⁶, and R⁷ are H; or three of R⁴, R⁵, R⁶, and R⁷ are H and one of R⁴,R⁵, R⁶, and R⁷ is selected from the group consisting of: halo, methoxy,and a C₁-C₃ alkyl; R³ is selected from the group consisting of:3-pyrrolidinyl, 4-piperidinyl, 3-piperidinyl, and 2-morpholinyl, whereinthe nitrogen in the ring of said 3-pyrrolidinyl, 4-piperidinyl,3-piperidinyl, or 2-morpholinyl is substituted with a C₁-C₃ alkyl or a—C(O)—O—C₁-C₄alkyl. In certain embodiments, a compound of formula XI maybe deprotected by removing said C₁-C₃ alkyl or —C(O)—O—C₁-C₄alkyl fromthe nitrogen in the ring of said 3-pyrrolidinyl, 4-piperidinyl,3-piperidinyl, or 2-morpholinyl using suitable reagents and conditionsto form a compound of formula I.

In another aspect, the present invention provides for methods oftreating a mammal suffering from a norepinephrine-mediated and/orserotonin-mediated disorder comprising administering to a mammal in needof such treatment a therapeutically effective amount of a compound offormula I.

In another aspect, the present invention provides for methods oftreating attention deficit hyperactivity disorder (ADHD) comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of formula I.

In another aspect, the present invention provides for methods oftreating a disorder or condition selected from neuropathic pain, stressurinary incontinence, depression, and schizophrenia, comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of formula I.

In another aspect, the present invention provides for methods oftreating fibromyalgia comprising administering to a mammal in need ofsuch treatment a therapeutically effective amount of a compound offormula I. In certain embodiments, the present invention provides formethods of treating fibromyalgia comprising administering to a mammal inneed of such treatment a therapeutically effective amount of1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole, or apharmaceutically acceptable salt therof. In certain embodiments, thepresent invention provides for methods of treating fibromyalgiacomprising administering to a mammal in need of such treatment atherapeutically effective amount of1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-tartrate.

In another aspect, the present invention provides for methods oftreating a mammal suffering from a norepinephrine-mediated and/orserotonin-mediated disorder comprising administering to a mammal in needof such treatment: (a) a compound of the formula I or a pharmaceuticallyacceptable salt thereof; (b) another pharmaceutically active compoundthat is an antidepressant or anti-anxiety agent, or a pharmaceuticallyacceptable salt thereof; and (c) a pharmaceutically acceptable carrier;wherein the active compounds “a” and “b” are present in amounts thatrender the composition effective in treating such disorder or condition.

In another aspect, the present invention provides for pharmaceuticalcompositions comprising: a therapeutically effective amount of acompound of formula I and a pharmaceutically acceptable carrier. Incertain embodiments, these compositions are useful in the treatment of anorepinephrine-mediated and/or serotonin-mediated disorder.

In another aspect, the present invention provides for crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole or apharmaceutically acceptable salt thereof. In one embodiment, the presentinvention provides for crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-tartrate. Incertain embodiments, crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-tartrate has aX-ray powder diffraction spectrum comprising the following 2-thetavalues ±0.1 measured using CuKα radiation: 22.0, 20.9, and 18.6. Incertain embodiments, crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-tartrate has aX-ray powder diffraction spectrum comprising the following 2-thetavalues ±0.1 measured using CuKα radiation: 13.2, 11.8, and 18.7.

In certain embodiments, crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-tartrate has aX-ray powder diffraction spectrum comprising the following 2-thetavalues ±0.1 measured using CuKα radiation: 37.8, 33.8, 16.8, 11.9, 13.2,29.0, 19.5, 27.6, 31.9, 25.5, 17.9, 23.8, 20.1, 26.0, 23.2, 29.6, 21.4,22.0, 20.9, and 18.6.

In certain embodiments, crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole edisylate has aX-ray powder diffraction spectrum comprising the following 2-thetavalues ±0.1 measured using CuKα radiation: 22.5, 20.0, and 21.2. Incertain embodiments, crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole edisylate has aX-ray powder diffraction spectrum comprising the following 2-thetavalues ±0.1 measured using CuKα radiation: 33.0, 15.7, 12.4, 14.1, 28.2,30.1, 17.3, 27.1, 19.0, 25.5, 24.1, 11.6, 22.5, 20.0, and 21.2.

In certain embodiments, crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole fumarate has aX-ray powder diffraction spectrum comprising the following 2-thetavalues ±0.1 measured using CuKα radiation: 24.6, 20.1, and 23.2. Incertain embodiments, crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole fumarate has aX-ray powder diffraction spectrum comprising the following 2-thetavalues ±0.1 measured using CuKα radiation: 12.7, 31.5, 11.7, 27.8, 22.4,26.6, 20.9, 17.2, 15.9, 29.5, 28.4, 25.3, 18.1, 24.6, 20.1, and 23.2.

In certain embodiments, crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole hydrobromide has aX-ray powder diffraction spectrum comprising the following 2-thetavalues ±0.1 measured using CuKα radiation: 23.8, 16.8, and 25.1. Incertain embodiments, crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole hydrobromide has aX-ray powder diffraction spectrum comprising the following 2-thetavalues ±0.1 measured using CuKα radiation: 18.0, 21.6, 38.0, 15.4, 14.1,30.4, 26.3, 33.5, 28.0, 25.6, 12.6, 29.3, 20.1, 24.0, 23.8, 16.8, 25.1,and 20.9.

In certain embodiments, crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole hemi L-tartrate hasa X-ray powder diffraction spectrum comprising the following 2-thetavalues ±0.1 measured using CuKα radiation: 34.5, 36.2, and 39.2. Incertain embodiments, crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole hemi L-tartrate hasa X-ray powder diffraction spectrum comprising the following 2-thetavalues ±0.1 measured using CuKα radiation: 10.3, 14.9, 15.7, 17.0, 19.0,20.5, 21.6, 22.7, 23.9, 24.7, 25.6, 27.7, 29.8, 32.6, 34.5, 36.2, and39.2.

In certain embodiments, crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-malate has aX-ray powder diffraction spectrum comprising the following 2-thetavalues ±0.1 measured using CuKα radiation: 21.9, 21.5, and 20.1. Incertain embodiments, crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-malate has aX-ray powder diffraction spectrum comprising the following 2-thetavalues ±0.1 measured using CuKα radiation: 36.8, 24.5, 26.3, 28.7, 12.2,25.2, 23.1, 18.2, 30.4, 27.3, 14.7, 20.9, 11.4, 19.2, 16.7, 21.9, 21.5,and 20.1.

In certain embodiments, crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole phosphate has aX-ray powder diffraction spectrum comprising the following 2-thetavalues ±0.1 measured using CuKα radiation: 21.2, 24.3, and 23.2. Incertain embodiments, crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole phosphate has aX-ray powder diffraction spectrum comprising the following 2-thetavalues ±0.1 measured using CuKα radiation: 12.1, 34.7, 14.0, 30.9, 25.6,29.3, 33.4, 16.9, 20.6, 15.6, 26.9, 22.8, 20.0, 27.3, 17.9, 21.2, 24.3,and 23.2.

In certain embodiments, crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole sulfate has a X-raypowder diffraction spectrum comprising the following 2-theta values ±0.1measured using CuKα radiation: 24.3, 20.2, and 12.1. In certainembodiments, crystalline1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole sulfate has a X-raypowder diffraction spectrum comprising the following 2-theta values ±0.1measured using CuKα radiation: 26.7, 27.6, 17.2, 21.4, 25.4, 29.7, 16.4,15.0, 20.0, 18.3, 23.0, 24.3, 20.2, and 12.1.

DEFINITIONS

The term “alkyl group” or “alkyl” includes straight and branched carbonchain radicals. The term “alkylene” refers to a diradical of anunsubstituted or substituted alkane. For example, a “C₁₋₆ alkyl” is analkyl group having from 1 to 6 carbon atoms. Examples of C₁-C₆straight-chain alkyl groups include, but are not limited to, methyl,ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. Examples ofbranched-chain alkyl groups include, but are not limited to, isopropyl,tert-butyl, isobutyl, etc. Examples of alkylene groups include, but arenot limited to, —CH₂—, —CH₂—CH₂—, —CH₂—CH(CH₃)—CH₂—, and —(CH₂)₁₋₃.Alkylene groups can be substituted with groups as set forth below foralkyl.

The term alkyl includes both “unsubstituted alkyls” and “substitutedalkyls,” the latter of which refers to alkyl moieties havingsubstituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents are independently selected fromthe group consisting of: halo, I, Br, Cl, F, —OH, —COOH,trifluoromethyl, —NH₂, —OCF₃, and O—C₁-C₃ alkyl.

Typical substituted alkyl groups thus are 2,3-dichloropentyl,3-hydroxy-5-carboxyhexyl, 2-aminopropyl, pentachlorobutyl,trifluoromethyl, methoxyethyl, 3-hydroxypentyl, 4-chlorobutyl,1,2-dimethyl-propyl, and pentafluoroethyl.

“Halo” includes fluoro, chloro, bromo, and iodo.

Some of the compounds in the present invention may exist asstereoisomers, including enantiomers, diastereomers, and geometricisomers. All of these forms, including (R), (S), epimers, diastereomers,cis, trans, syn, anti, solvates (including hydrates), tautomers, andmixtures thereof, are contemplated in the compounds of the presentinvention.

BRIEF DESCRIPTIONS OF THE DRAWINGS

FIGS. 1-8 are powder x-ray diffraction (PXRD) spectra of:1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-tartrate (FIG.1); 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole edisylate (FIG.2); 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole fumarate (FIG.3); 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole hydrobromide(FIG. 4); 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazolehemi-L-tartrate (FIG. 5);1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-malate (FIG. 6);1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole phosphate (FIG. 7);and 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole sulfate (FIG.8).

FIGS. 9-16 are differential scanning calorimetry thermal profiles of:1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-tartrate (FIG.9); 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole edisylate (FIG.10); 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole fumarate (FIG.11); 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole hydrobromide(FIG. 12); 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazolehemi-L-tartrate (FIG. 13);1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-malate (FIG. 14);1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole phosphate (FIG.15); and 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole sulfate(FIG. 16).

FIG. 17 is a calculated powder x-ray diffraction (PXRD) spectrum of:1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-tartrate.

DETAILED DESCRIPTION OF THE INVENTION

Preparation of Compounds

Compounds of the present invention (e.g., compounds of Formula I) can beprepared by applying synthetic methodology known in the art andsynthetic methodology outlined in the schemes set forth below.

A phenylhydrazine b (e.g., 2-fluorophenylhydrazine) orpyridinylhydrazine (e.g., 2-hydrazinopyridine) that has been treatedwith or without a base such as N,N-diisopropylethylamine ortriethylamine in a suitable solvent (e.g., ethanol or tetrahydrofuran(THF)) is reacted with the anhydride a (e.g., isatoic anhydride) to givethe hydrazide c (e.g., 2-amino-benzoic acidN′-(2-fluoro-phenyl)-hydrazide). c is then acidified and reacted withsodium nitrite, followed by ethanol to generate the indazole d (e.g.,1-(2-fluoro-phenyl)-1H-indazol-3-ol).

A mixture of the 1-(2-fluoro-phenyl)-1H-indazol-3-ol d, a compound e(LG-O-L-R³-PG) and a base such as a hydride base (e.g., sodium hydride,potassium hydride),2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro1,3,2-diazaphosphorine(BEMP),2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro1,3,2-diazaphosphorineon polystyrene (PS-BEMP resin), Na₂CO₃, K₂CO₃, or Cs₂CO₃ in anhydrousDMF (dimethylformamide) are reacted to provide f (e.g.,4-[1-(2-fluoro-phenyl)-1H-indazol-3-yloxy]-piperidine-1-carboxylic acidtert-butyl ester). LG of e is a suitable leaving group such asmethanesulfonyloxy, benzenesulfonyloxy, toluene-4-sulfonyloxy, andtrifluoromethanesulfonyloxy. PG of e is a suitable amine protectinggroup such as t-butyl-ester (BOC). Those of skill in the art willrecognize that a wide variety of protecting groups in addition to BOCcan be used as a suitable amine protecting group for R³ (see e.g.,Greene and Wuts, Protective Groups in Organic Synthesis,Wiley-Interscience; 3rd edition (1999). Thus, an example of e is4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester. ThePG substituent of f is then removed to provide g (e.g.,1-(2-Fluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazole). Groups such asBOC may be hydrolyzed under acidic conditions.

Scheme 2 depicts the synthesis of the anhydride a. a (e.g.,6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione) can be synthesized byreacting a 2-aminobenzoic acid j (e.g., 2-amino-5-fluorobenzoic acid)with a base such as sodium carbonate in water, followed by the additionof a phosgene solution in toluene.

In Scheme 3, an alternative synthetic route to c is depicted. A2-amino-benzoic acid j (e.g., 2-amino-5-chloro-benzoic acid) is reactedwith a hydrazine b (e.g., 2,5-difluoro-phenyl)-hydrazine) in thepresence of a coupling reagent such as1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI),dicyclohexylcarbodiimide (DCC), 1,1′-carbonyldiimidazole (CDI) and abase such as dimethylaminopyridine (DMAP), N,N-diisopropylethylamine(DIPEA), or triethylamine to afford c (e.g., 2-amino-5-chloro-benzoicacid N′-(2,5-difluoro-phenyl)-hydrazide). Alternatively, j can bereacted with b and HOBT (1-hydroxybenzotriazole hydrate) in a solventsuch as dry THF (tetrahydrofuran). N-Me-morpholine (NMM) is then addedand before adding EDAC-HCl(1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride) toprovide compound c.

Scheme 4 depicts the synthesis of the 1H-pyrazolo[3,4-b]pyridine q. Anicotinoylchloride k (e.g., 2-chloronicotinoyl chloride) is reacted witha hydrazine m (e.g., phenylhydrazine) and a base such as triethylaminein a solvent such as anhydrous methylene chloride to give o (e.g.,1-phenyl-1H-pyrazolo[3,4-b]pyridin-3-ol). The compound o is thencyclized by heating at 175° C. to provide p. p is reacted as in thetransformation of d to g in Scheme 1 to provide q.

Evaluation of Compounds

Compounds of the present invention (e.g., compounds of Formula I andpharmaceutically acceptable salts thereof) can be assayed for theirability to inhibit a norepinephrine transporter and/or a serotonintransporter.

The ability of the compounds of the present invention to inhibit anorepinephrine transporter and/or a serotonin transporter can bedetermined using conventional radioligand receptor transport assays. Thereceptors can be heterologously expressed in cell lines and experimentsconducted in membrane preparations from the cell lines that express anorepinephrine transporter and/or a serotonin transporter.

In certain embodiments, the compounds of formula I may be assayed fortheir ability to alleviate capsaicin-induced mechanical allodynia in arat (e.g., Sluka, K A, (2002) J of Neuroscience, 22(13): 5687-5693). Forexample, a rat model of capsaicin-induced mechanical allodynia) can becarried out as follows:

On day 0, male Sprague-Dawley rats (˜150 g) in the dark cycle are placedin suspended wire-bottom cages and allowed to acclimate for 0.5 h in adarkened, quiet room. The day 0 paw withdrawal threshold (PWT) isdetermined on the left hind paw by Von Frey hair assessment using theDixon up and down method. After assessment, the plantar muscle of theright hind paw is injected with 100 μl capsaicin (0.25% in 10% ethanol,10% Tween 80, in sterile saline). On day 6 the PWT of the left hindpaw(contralateral from injection site) is determined for each animal.Animals from the day 6 prereads with PWT≦11.7 g are considered allodynicresponders and are regrouped so that each cage had similar mean PWTvalues. On day 7, responders are dosed (e.g., orally, intraperitoneally,and subcutaneously, etc.) with 10 ml/kg vehicle (0.5%HPMC(hydroxy-propylmethylcellulose)/0.2% Tween™ 80), or vehicle pluscompound. The contralateral PWT values are determined at 2 hours (or atabout the time corresponding to the estimated C_(max)) after the singledose, with the investigator blinded to the dosing scheme. Those of skillin the art can determine the appropriate time to determine thecontralateral PWT value (e.g., 1 hour, 2 hours, etc.).

For each animal, the day 6 PWT value is subtracted from the 2 hour PWTvalue to give a delta PWT value that represents the change in PWT due tothe 2 hour drug treatment. In addition, the day 6 PWT is subtracted fromthe day 0 PWT to give the baseline window of allodynia present in eachanimal. To determine % inhibition of allodynia of each animal normalizedfor vehicle controls, the following formula is used:

${\%\mspace{14mu}{Inhibiton}\mspace{14mu}{of}\mspace{14mu}{Allodynia}} = {100 \times {\frac{\left( {{{Delta}\mspace{11mu}{{PWT}({drug})}} - {{mean}\mspace{14mu}{Delta}\mspace{14mu}{PWT}\mspace{11mu}({vehicle})}} \right)/}{\left( {{Baseline} - {{mean}\mspace{14mu}{Delta}\mspace{14mu}{PWT}\mspace{11mu}({vehicle})}} \right)}.}}$Pharmaceutically Acceptable Salts and Solvates

The compounds to be used in the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms are intended to beencompassed within the scope of the present invention.

The compounds of the present invention (e.g., compounds of Formula I)are capable of further forming both pharmaceutically acceptable salts,including but not limited to acid addition and/or base salts.Pharmaceutically acceptable salts of the compounds of formula (I)include the acid addition and base salts (including disalts) thereof.Examples of suitable salts can be found for example in Stahl andWermuth, Handbook of Pharmaceutical Salts: Properties, Selection, andUse, Wiley-V C H, Weinheim, Germany (2002); and Berge et al.,“Pharmaceutical Salts,” J. of Pharmaceutical Science, 1977; 66:1-19.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include non-toxic salts derived from inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,phosphorus, and the like, as well as the salts derived from organicacids, such as aliphatic mono- and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Suchsalts thus include the acetate, aspartate, benzoate, besylate(benzenesulfonate), bicarbonate/carbonate, bisulfate, caprylate,camsylate (camphor sulfonate), chlorobenzoate, citrate,edisylate(1,2-ethane disulfonate), dihydrogenphosphate, dinitrobenzoate,esylate (ethane sulfonate), fumarate, gluceptate, gluconate,glucuronate, hibenzate, hydrochloride/chloride, hydrobromide/bromide,hydroiodide/iodide, isobutyrate, monohydrogen phosphate, isethionate,D-lactate, L-lactate, malate, maleate, malonate, mandelate, mesylate(methanesulfonate), metaphosphate, methylbenzoate, methylsulfate,2-napsylate (2-naphthalene sulfonate), nicotinate, nitrate, orotate,oxalate, palmoate, phenylacetate, phosphate, phthalate, propionate,pyrophosphate, pyrosulfate, saccharate, sebacate, stearate, suberate,succinate sulfate, sulfite, D-tartrate, L-tartrate, tosylate (toluenesulfonate), and xinafoate salts, and the like of compounds of Formula I.Also contemplated are the salts of amino acids such as arginate,gluconate, galacturonate, and the like.

Acid addition salts of the basic compounds may be prepared by contactingthe free base form with a sufficient amount of the desired acid toproduce the salt. The free base form may be regenerated by contactingthe salt form with a base and isolating the free base. The free baseforms differ from their respective salt forms somewhat in certainphysical properties such as solubility in polar solvents.

Pharmaceutically acceptable base addition salts may be formed withmetals or amines, such as alkali and alkaline earth metal hydroxides, orof organic amines. Examples of metals used as cations are aluminum,calcium, magnesium, potassium, sodium, and the like. Examples ofsuitable amines include arginine, choline, chloroprocaine,N,N′-dibenzylethylenediamine, diethylamine, diethanolamine, diolamine,ethylenediamine (ethane-1,2-diamine), glycine, lysine, meglumine,N-methylglucamine, olamine, procaine (benzathine), and tromethamine.

The base addition salts of acidic compounds may be prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt. The free acid form may be regenerated bycontacting the salt form with an acid and isolating the free acid. Thefree acid forms may differ from their respective salt forms somewhat incertain physical properties such as solubility in polar solvents.

Pharmaceutical Compositions and Methods of Administration

The present invention also provides for pharmaceutical compositionscomprising a therapeutically effective amount of a compound of FormulaI, or a pharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier, diluent, or excipient therefor. Thephrase “pharmaceutical composition” refers to a composition suitable foradministration in medical or veterinary use. The phrase “therapeuticallyeffective amount” means an amount of a compound, or a pharmaceuticallyacceptable salt thereof, sufficient to inhibit, halt, or allow animprovement in the disease being treated when administered alone or inconjunction with another pharmaceutical agent or treatment in aparticular subject or subject population. For example in a human orother mammal, a therapeutically effective amount can be determinedexperimentally in a laboratory or clinical setting, for the particulardisease and subject being treated.

It should be appreciated that determination of proper dosage forms,dosage amounts, and routes of administration is within the level ofordinary skill in the pharmaceutical and medical arts, and is describedbelow.

A compound of the present invention can be formulated as apharmaceutical composition in the form of a syrup, an elixir, asuspension, a powder, a granule, a tablet, a capsule, a lozenge, atroche, an aqueous solution, a cream, an ointment, a lotion, a gel, anemulsion, etc. Preferably, a compound of the present invention willcause a decrease in symptoms or a disease indicia associated with anorepinephrine-mediated and/or serotonin-mediated disorder as measuredquantitatively or qualitatively.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances, which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

The powders and tablets contain from 1% to 95% (w/w) of the activecompound. In certain embodiments, the active compound ranges from 5% to70% (w/w). Suitable carriers are magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well-known suspending agents.

Also included are solid form preparations, which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampules. Also, the unit dosage form can be a capsule, tablet, cachet, orlozenge itself, or it can be the appropriate number of any of these inpackaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 1000 mg, preferably 1.0 mg to 100 mg,or from 1% to 95% (w/w) of a unit dose, according to the particularapplication and the potency of the active component. For example, a unitdose may contain 10, 15, 20, 25, 30, 40, or 50 mg of a compound of thepresent invention. The composition can, if desired, also contain othercompatible therapeutic agents.

Pharmaceutically acceptable carriers are determined in part by theparticular composition being administered, as well as by the particularmethod used to administer the composition. Accordingly, there are a widevariety of suitable formulations of pharmaceutical compositions of thepresent invention (see, e.g., Remington: The Science and Practice ofPharmacy, 20th ed., Gennaro et al. Eds., Lippincott Williams andWilkins, 2000).

A compound of the present invention, alone or in combination with othersuitable components, can be made into aerosol formulations (i.e., theycan be “nebulized”) to be administered via inhalation. Aerosolformulations can be placed into pressurized acceptable propellants, suchas dichlorodifluoromethane, propane nitrogen, and the like.

Formulations suitable for parenteral administration, such as, forexample, by intravenous, intramuscular, intradermal, and subcutaneousroutes, include aqueous and non-aqueous, isotonic sterile injectionsolutions, which can contain antioxidants, buffers, bacteriostats, andsolutes that render the formulation isotonic with the blood of theintended recipient, and aqueous and nonaqueous sterile suspensions thatcan include suspending agents, solubilizers, thickening agents,stabilizers, and preservatives. In the practice of the presentinvention, compositions can be administered, for example, by intravenousinfusion, orally, topically, intraperitoneally, intravesically orintrathecally. The formulations of compounds can be presented inunit-dose or multi-dose sealed containers, such as ampules and vials.Injection solutions and suspensions can be prepared from sterilepowders, granules, and tablets of the kind previously described.

The dose administered to a subject, in the context of the presentinvention should be sufficient to affect a beneficial therapeuticresponse in the subject over time. The term “subject” refers to a memberof the class Mammalia. Examples of mammals include, without limitation,humans, primates, chimpanzees, rodents, mice, rats, rabbits, horses,livestock, dogs, cats, sheep, and cows. In certain embodiments, the“subject” is a human.

The dose will be determined by the efficacy of the particular compoundemployed and the condition of the subject, as well as the body weight orsurface area of the subject to be treated. The size of the dose alsowill be determined by the existence, nature, and extent of any adverseside effects that accompany the administration of a particular compoundin a particular subject. In determining the effective amount of thecompound to be administered in the treatment or prophylaxis of thedisease being treated, the physician can evaluate factors such as thecirculating plasma levels of the compound, compound toxicities, and/orthe progression of the disease, etc. In general, the dose equivalent ofa compound is from about 1 μg/kg to 100 mg/kg for a typical subject.Many different administration methods are known to those of skill in theart.

For administration, compounds of the present invention can beadministered at a rate determined by factors that can include, but arenot limited to, the pharmacokinetic profile of the compound,contraindicated drugs, and the side effects of the compound at variousconcentrations, as applied to the mass and overall health of thesubject. Administration can be accomplished via single or divided doses.

An example of a typical tablet includes the following:

TABLET FORMULATION EXAMPLE 1 Tablet Formulation Ingredient Amount ACompound of Formula I 50 mg Lactose 80 mg Cornstarch (for mix) 10 mgCornstarch (for paste)  8 mg Magnesium Stearate (1%)  2 mg 150 mg The compounds of the present invention (e.g., a compound of Formula I,or a pharmaceutically acceptable salt thereof) can be mixed with thelactose and cornstarch (for mix) and blended to uniformity to a powder.The cornstarch (for paste) is suspended in 6 ml of water and heated withstirring to form a paste. The paste is added to the mixed powder, andthe mixture is granulated. The wet granules are passed through a No. 8hard screen and dried at 50° C. The mixture is lubricated with 1%magnesium stearate and compressed into a tablet. The tablets areadministered to a patient at the rate of 1 to 4 each day for treatmentof a norepinephrine-mediated and/or serotonin-mediated disorder.Methods for Treating Norepinephrine-Mediated and/or Serotonin-MediatedDisorders

The compounds of the present invention and pharmaceutical compositionscomprising a compound of the present invention can be administered totreat a subject suffering from a norepinephrine-mediated and/orserotonin-mediated disorder, including central nervous disorders, whichis alleviated by the inhibition of a norepinephrine transporters and/orserotonin transporters.

Norepinephrine-mediated and/or serotonin-mediated disorders can betreated prophylactically, acutely, and chronically using compounds ofthe present invention, depending on the nature of the disease.Typically, the host or subject in each of these methods is human,although other mammals can also benefit from the administration of acompound of the present invention.

In therapeutic applications, the compounds of the present invention canbe prepared and administered in a wide variety of oral and parenteraldosage forms. The term “administering” refers to the method ofcontacting a compound with a subject. Thus, the compounds of the presentinvention can be administered by injection, that is, intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally,parentally, or intraperitoneally. Also, the compounds described hereincan be administered by inhalation, for example, intranasally.Additionally, the compounds of the present invention can be administeredtransdermally, topically, and via implantation. In certain embodiments,the compounds of the present invention are delivered orally. Thecompounds can also be delivered rectally, bucally, intravaginally,ocularly, or by insufflation.

The compounds utilized in the pharmaceutical method of the invention canbe administered at the initial dosage of about 0.001 mg/kg to about 100mg/kg daily. In certain embodiments, the daily dose range is from about0.1 mg/kg to about 10 mg/kg. The dosages, however, may be varieddepending upon the requirements of the subject, the severity of thedisease being treated, and the compound being employed. Determination ofthe proper dosage for a particular situation is within the skill of thepractitioner. Generally, treatment is initiated with smaller dosages,which are less than the optimum dose of the compound. Thereafter, thedosage is increased by small increments until the optimum effect undercircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired. Theterm “treatment” includes the acute, chronic, or prophylacticdiminishment or alleviation of at least one symptom or characteristicassociated with or caused by the disease being treated. For example,treatment can include diminishment of several symptoms of a disease,inhibition of the pathological progression of a disease, or completeeradication of a disease.

The present invention also relates to a method of treating anorepinephrine-mediated and/or serotonin-mediated disorder comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of formula I. Examples ofnorepinephrine-mediated and/or serotonin-mediated disorders includefibromyalgia, single episodic or recurrent major depressive disorders,dysthymic disorders, depressive neurosis and neurotic depression,melancholic depression including anorexia, weight loss, insomnia, earlymorning waking or psychomotor retardation; atypical depression (orreactive depression) including increased appetite, hypersomnia,psychomotor agitation or irritability, seasonal affective disorder andpediatric depression; bipolar disorders or manic depression, forexample, bipolar I disorder, bipolar II disorder and cyclothymicdisorder; conduct disorder; attention deficit hyperactivity disorder(ADHD); disruptive behavior disorder; behavioral disturbances associatedwith mental retardation, autistic disorder, and conduct disorder;anxiety disorders such as panic disorder with or without agoraphobia,agoraphobia without history of panic disorder, specific phobias, forexample, specific animal phobias, social anxiety, social phobia,obsessive-compulsive disorder, stress disorders including post-traumaticstress disorder and acute stress disorder, and generalized anxietydisorders; borderline personality disorder; schizophrenia and otherpsychotic disorders, for example, schizophreniform disorders,schizoaffective disorders, delusional disorders, brief psychoticdisorders, shared psychotic disorders, psychotic disorders withdelusions or hallucinations, psychotic episodes of anxiety, anxietyassociated with psychosis, psychotic mood disorders such as severe majordepressive disorder; mood disorders associated with psychotic disorderssuch as acute mania and depression associated with bipolar disorder;mood disorders associated with schizophrenia; delirium, dementia, andamnestic and other cognitive or neurodegenerative disorders, such asParkinson's disease (PD), Huntington's disease (HD), Alzheimer'sdisease, senile dementia, dementia of the Alzheimer's type, memorydisorders, loss of executive function, vascular dementia, and otherdementias, for example, due to HIV disease, head trauma, Parkinson'sdisease, Huntington's disease, Pick's disease, Creutzfeldt-Jakobdisease, or due to multiple etiologies; movement disorders such asakinesias, dyskinesias, including familial paroxysmal dyskinesias,spasticities, Tourette's syndrome, Scott syndrome, palsys (e.g., Bell'spalsy, cerebral palsy, birth palsy, brachial palsy, wasting palsy,ischemic palsy, progressive bulbar palsy and other palsys), andakinetic-rigid syndrome; extra-pyramidal movement disorders such asmedication-induced movement disorders, for example, neuroleptic-inducedParkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acutedystonia, neuroleptic-induced acute akathisia, neuroleptic-inducedtardive dyskinesia and medication-induced postural tremour; chemicaldependencies and addictions (e.g., dependencies on, or addictions to,alcohol, heroin, cocaine, benzodiazepines, nicotine, or phenobarbitol)and behavioral addictions such as an addiction to gambling; and oculardisorders such as glaucoma and ischemic retinopathy.

In one particular embodiment, patients suffering from fibromyalgia areadministered a therapeutically effective amount of a compound of formulaI, or a pharmaceutically acceptable salt thereof. Patients sufferingfrom fibromyalgia typically exhibit a history of widespread pain, andthe presence of pain at 11 out of 18 points upon palpatation (see e.g.,Wolfe et al. (1990) Arthritis Rheum. 33:160-172). Fibromyalgia patientsgenerally display pain perception abnormalities in the form of bothallodynia (pain from innocuous stimulation) and hyperalgesia (anincreased sensitivity to a painful stimulation).

Fibromyalgia patients typically also exhibit a range of other symptoms,including sleep disturbance and fatigue. Although less common than pain,fatigue, and sleep problems, a variety of other symptoms may occur aswell. These include headaches, morning stiffness, difficultyconcentrating, a circulatory problem that affects the small bloodvessels of the skin (Raynaud's phenomenon), and irritable bowelsyndrome. As with many conditions that cause chronic pain, anxiety anddepression are common in fibromyalgia patients and may make symptomsworse. Symptoms may tend to come and go. There can be periods when thesymptoms are constant (flares), that may be followed by periods when thesymptoms are absent (remissions). Some fibromyalgia patients find thatcold, damp weather, emotional stress, overexertion, and other factorsexacerbate their symptoms.

A more specific embodiment of the present invention relates to the abovemethod wherein the disorder or condition that is being treated isselected from major depression, single episode depression, recurrentdepression, child abuse induced depression, postpartum depression,dysthymia, cyclothymia and bipolar disorder.

Another more specific embodiment of the present invention relates to theabove method wherein the disorder or condition that is being treated isselected from schizophrenia, schizoaffective disorder, delusionaldisorder, substance-induced psychotic disorder, brief psychoticdisorder, shared psychotic disorder, psychotic disorder due to a generalmedical condition, and schizophreniform disorder.

Another more specific embodiment of the present invention relates to theabove method wherein the disorder or condition that is being treated isselected from autism, pervasive development disorder, and attentiondeficit hyperactivity disorder.

Another more specific embodiment of the present invention relates to theabove method wherein the disorder or condition that is being treated isselected from generalized anxiety disorder, panic disorder,obsessive-compulsive disorder, post-traumatic stress disorder, andphobias, including social phobia, agoraphobia, and specific phobias.

Another more specific embodiment of the present invention relates to theabove method wherein the disorder or condition that is being treated isselected from movement disorders such as akinesias, dyskinesias,including familial paroxysmal dyskinesias, spasticities, Tourette'ssyndrome, Scott syndrome, palsys (e.g., Bell's palsy, cerebral palsy,birth palsy, brachial palsy, wasting palsy, ischemic palsy, progressivebulbar palsy and other palsys), and akinetic-rigid syndrome; andextra-pyramidal movement disorders such as medication-induced movementdisorders, for example, neuroleptic-induced Parkinsonism, neurolepticmalignant syndrome, neuroleptic-induced acute dystonia,neuroleptic-induced acute akathisia, neuroleptic-induced tardivedyskinesia and medication-induced postural tremor.

Another more specific embodiment of the present invention relates to theabove method wherein the disorder or condition that is being treated ispain. Pain refers to acute as well as chronic pain. Acute pain isusually short-lived and is associated with hyperactivity of thesympathetic nervous system. Examples are postoperative pain andallodynia. Chronic pain is usually defined as pain persisting from 3 to6 months and includes somatogenic pain and psychogenic pain. Other painis nociceptive.

Examples of the types of pain that can be treated with the compounds offormula I of the present invention and their pharmaceutically acceptablesalts include pain resulting from soft tissue and peripheral damage,such as acute trauma, pain associated with osteoarthritis and rheumatoidarthritis, musculo-skeletal pain, such as pain experienced after trauma;spinal pain, dental pain, myofascial pain syndromes, episiotomy pain,and pain resulting from burns; deep and visceral pain, such as heartpain, muscle pain, eye pain, orofacial pain, for example, odontalgia,abdominal pain, gynaecological pain, for example, dysmenorrhoea, labourpain and pain associated with endometriosis; pain associated with nerveand root damage, such as pain associated with peripheral nervedisorders, for example, nerve entrapment and brachial plexus avulsions,amputation, peripheral neuropathies, tic douloureux, atypical facialpain, nerve root damage, trigeminal neuralgia, neuropathic lower backpain, HIV related neuropathic pain, cancer related neuropathic pain,diabetic neuropathic pain, and arachnoiditis; neuropathic andnon-neuropathic pain associated with carcinoma, often referred to ascancer pain; central nervous system pain, such as pain due to spinalcord or brain stem damage; lower back pain; sciatica; phantom limb pain,headache, including migraine and other vascular headaches, acute orchronic tension headache, cluster headache, temperomandibular pain andmaxillary sinus pain; pain resulting from ankylosing spondylitis andgout; pain caused by increased bladder contractions; post operativepain; scar pain; and chronic non-neuropathic pain such as painassociated with fibromyalgia, HIV, rheumatoid and osteoarthritis,arthralgia and myalgia, sprains, strains and trauma such as brokenbones; and post surgical pain.

Still other pain is caused by injury or infection of peripheral sensorynerves. It includes, but is not limited to pain from peripheral nervetrauma, herpes virus infection, diabetes mellitus, fibromyalgia,causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis.Neuropathic pain is also caused by nerve damage from chronic alcoholism,human immunodeficiency virus infection, hypothyroidism, uremia, orvitamin deficiencies. Neuropathic pain includes, but is not limited topain caused by nerve injury such as, for example, the pain diabeticssuffer from.

Psychogenic pain is that which occurs without an organic origin such aslow back pain, atypical facial pain, and chronic headache.

Other types of pain are: inflammatory pain, osteoarthritic pain,trigeminal neuralgia, cancer pain, diabetic neuropathy, restless legsyndrome, acute herpetic and postherpetic neuralgia, causalgia, brachialplexus avulsion, occipital neuralgia, gout, phantom limb, burn, andother forms of neuralgia, neuropathic and idiopathic pain syndrome.

Another more specific embodiment of the present invention relates to theabove method wherein the disorder or condition that is being treated isselected from delirium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Parkinson's disease (PD),Huntington's disease (HD), Alzheimer's disease, senile dementia,dementia of the Alzheimer's type, memory disorders, loss of executivefunction, vascular dementia, and other dementias, for example, due toHIV disease, head trauma, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeldt-Jakob disease, or due to multipleetiologies.

The compounds of the present invention can be co-administered to asubject. The term “co-administered” means the administration of two ormore different pharmaceutical agents or treatments (e.g., radiationtreatment) that are administered to a subject by combination in the samepharmaceutical composition or separate pharmaceutical compositions. Thusco-administration involves administration at the same time of a singlepharmaceutical composition comprising two or more pharmaceutical agentsor administration of two or more different compositions to the samesubject at the same or different times. For example, a subject that isadministered a first dosage that comprises a compound of the presentinvention at 8 a.m. and then is administered a second therapeutic agentat 1-12 hours later, e.g., 6 p.m., of that same day has beenco-administered with a compound of the present invention and the secondtherapeutic agent. Alternatively, for example, a subject could beadministered with a single dosage comprising a compound of the presentinvention and a second therapeutic agent at 8 a.m. has beenco-administered with a compound of the present invention and the secondtherapeutic agent.

The compounds of the present invention may further be co-administeredfor the treatment of fibromyalgia with one or more agents useful fortreating one or more indicia of fibromyalgia selected from the groupconsisting of: non-steroidal anti-inflammatory agents (hereinafterNSAID's) such as piroxicam, loxoprofen, diclofenac, propionic acids suchas naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen,ketorolac, nimesulide, acetominophen, fenamates such as mefenamic acid,indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone,salicylates such as aspirin, COX-2 inhibitors such as CELEBREX®(celecoxib), BEXTRA® (valdecoxib) and etoricoxib: steroids, cortisone,prednisone, muscle relaxants including cyclobenzaprine and tizanidine;hydrocodone, dextropropoxyphene, lidocaine, opioids, morphine, Fentanyl,tramadol, codeine, Paroxetine (PAXIL®), Diazepam, Femoxetine,Carbamazepine, Milnacipran (IXEL®), Vestra®, Venlafaxine (EFFEXOR®),Duloxetine (CYMBALTA®), Topisetron (NAVOBAN®), Interferon alpha(Veldona), Cyclobenzaprine, CPE-215, Sodium oxbate (XYREM®), Celexa™(citalopram HBr), ZOLOFT® (sertraline HCl), antidepressants, tricyclicantidepressants, Amitryptyline, Fluoxetine (PROZAC®), topiramate,escitalopram, benzodiazepenes including diazepam, bromazepam andtetrazepam, mianserin, clomipramine, imipramine, topiramate, andnortriptyline. The compound of the present invention may also beco-administered with alpha-2-delta ligands. Examples of alpha-2-deltaligands for use with the present invention are those compounds generallyor specifically disclosed in U.S. Pat. No. 4,024,175, particularlygabapentin (NEURONTIN®), EP641330, particularly pregabalin (LYRICA®),U.S. Pat. No. 5,563,175, WO9733858, WO9733859, WO9931057, WO9931074,WO9729101, WO02085839, particularly[(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,WO9931075, particularly3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one andC-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, WO9921824,particularly (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-aceticacid, WO0190052, WO0128978, particularly(1α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,EP0641330, WO9817627, WO0076958, particularly(3S,5R)-3-aminomethyl-5-methyl-octanoic acid, PCT/IB03/00976,particularly (3S,5R)-3-amino-5-methyl-heptanoic acid,(3S,5R)-3-amino-5-methyl-nonanoic acid and(3S,5R)-3-Amino-5-methyl-octanoic acid, EP1178034, EP1201240, WO9931074,WO03000642, WO0222568, WO0230871, WO0230881, WO02100392, WO02100347,WO0242414, WO0232736 and WO0228881, and pharmaceutically acceptablesalts and solvates thereof, all of which are incorporated herein byreference.

For the treatment of depression, anxiety, schizophrenia or any of theother disorders and conditions referred to above in the descriptions ofthe methods and pharmaceutical compositions of the present invention,the compounds of the present invention can be used in conjunction withone or more other antidepressants or anti-anxiety agents. Examples ofclasses of antidepressants that can be used in combination with theactive compounds of the present invention include norepinephrinereuptake inhibitors, selective serotonin reuptake inhibitors (SRIs),NK-1 receptor antagonists, monoamine oxidase inhibitors (MAOIs),reversible inhibitors of monoamine oxidase (RIMAs), serotonin andnoradrenaline reuptake inhibitors (SNRIs), corticotropin releasingfactor (CRF) antagonists, α-adrenoreceptor antagonists, alpha-2-deltaligands (A2D) (e.g., NEURONTIN®, and LYRICA®,[(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one andC-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,(3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid,(1α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,(3S,5R)-3-aminomethyl-5-methyl-octanoic acid,(3S,5R)-3-amino-5-methyl-heptanoic acid,(3S,5R)-3-amino-5-methyl-nonanoic acid and(3S,5R)-3-amino-5-methyl-octanoic acid, etc.)), and atypicalantidepressants. Suitable norepinephrine reuptake inhibitors includetertiary amine tricyclics and secondary amine tricyclics. Suitabletertiary amine tricyclics and secondary amine tricyclics includeamitriptyline, clomipramine, doxepin, imipramine, trimipramine,dothiepin, butripyline, iprindole, lofepramine, nortriptyline,protriptyline, amoxapine, desipramine and maprotiline. Suitableselective serotonin reuptake inhibitors include fluoxetine, fluvoxamine,paroxetine, citalopram, and sertraline. Examples of monoamine oxidaseinhibitors include isocarboxazid, phenelzine, and tranylcyclopramine.Suitable reversible inhibitors of monoamine oxidase include moclobemide.Suitable serotonin and noradrenaline reuptake inhibitors of use in thepresent invention include venlafaxine and duloxetine. Suitable CRFantagonists include those compounds described in International PatentApplication Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 andWO 94/13677. Suitable atypical antidepressants include bupropion,lithium, nefazodone, trazodone and viloxazine. Suitable NK-1 receptorantagonists include those referred to in World Patent Publication WO01/77100. Suitable A2D ligands include those referred to in World PatentPublications WO 99/21824, WO 01/90052, WO 01/28978, WO 98/17627, WO00/76958, and WO 03/082807, and specifically NEURONTIN® and LYRICA®.

Suitable classes of anti-anxiety agents that can be used in combinationwith the active compounds of the present invention includebenzodiazepines and serotonin IA (5-HT_(IA)) agonists or antagonists,especially 5-HT_(IA) partial agonists, and corticotropin releasingfactor (CRF) antagonists. Suitable benzodiazepines include alprazolam,chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam,lorazepam, oxazepam, and prazepam. Suitable 5-HT_(IA) receptor agonistsor antagonists include buspirone, flesinoxan, gepirone and ipsapirone.

Suitable antipsychotic agents include both conventional and atypicalantipsychotics.

Conventional antipsychotics are antagonists of dopamine (D₂) receptors.The atypical antipsychotics also have D₂ antagonistic properties butpossess different binding kinetics to these receptors and activity atother receptors, particularly 5-HT_(2A), 5-HT_(2C) and 5-HT_(2D)(Schmidt B et al, Soc. Neurosci. Abstr. 24:2177, 1998).

The class of atypical antipsychotics includes clozapine (CLOZARIL®),8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine (U.S.Pat. No. 3,539,573); risperidone (RISPERDAL®),3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one(U.S. Pat. No. 4,804,663); olanzapine (ZYPREXA®),2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine(U.S. Pat. No. 5,229,382); quetiapine (SEROQUEL®),5-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]ethanol(U.S. Pat. No. 4,879,288); aripiprazole (ABILIFY®),7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydrocarbostyril and7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro-2(1H)-quinolinone(U.S. Pat. Nos. 4,734,416 and 5,006,528); sertindole,1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]imidazolidin-2-one(U.S. Pat. No. 4,710,500); amisulpride (U.S. Pat. No. 4,410,822); andziprasidone (GEODON®),5-[2-[4-(1,2-benzisothiazol-3-yl)piperazin-3-yl]ethyl]-6-chloroindolin-2-onehydrochloride hydrate (U.S. Pat. No. 4,831,031).

EXAMPLES Example 1 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazolehydrochloride

To a slurry of 2-fluorophenylhydrazine hydrochloride (40.1 g, 246.7mmol) in 411 ml EtOH was added di-isopropylethylamine (47.27 ml, 271.4mmol) followed by solid isatoic anhydride (40.0 g, 246.7 mmol). Theslurry was heated to reflux. Upon reflux, all the solids went intosolution and refluxing was continued for 1.5 hours. The reaction mixturewas allowed to cool to room temperature and stood overnight. The solidthat precipitated was filtered and washed with EtOH (ethanol). Thefiltrate was concentrated to dryness and the remaining material wastaken up in EtOAc (ethyl acetate), washed with water and dried overNa₂SO₄. The EtOAc solution was concentrated and the remaining oil wastaken up in a minimal amount of ether. The ether solution was thentriturated with heptane. The solid recovered was combined with the aboveto give 34.89 g of the hydrazide. The hydrazide was slurried into 307 mlof 1M HCl solution. The slurry was cooled to 0° C. and sodium nitrite(19.62 g, 284.4 mmol) in 100 ml water was added. Next 582 ml of EtOH wasadded and the slurry was refluxed for 2 hours then allowed to standovernight at room temperature. The resulting slurry was filtered andwashed with EtOH. The filtrate was concentrated down to give more solid.After combining with the 1st batch of solid, the material wasrecrystallized in 95:5 EtOH:i-PrOH (isopropanol) to give 23.45 g of1-(2-fluoro-phenyl)-1H-indazol-3-ol (Intermediate 1). MS (APCI): 229(M+1, 100%).

To a solution of t-butyl 4-hydroxy-1-piperidinecarboxylate (0.94 g, 4.66mmol) and methanesulfonyl chloride (0.43 ml, 5.56 mmol) in 10 ml ofanhydrous CH₂Cl₂ at 0° C. was added triethylamine (0.71 ml, 5.09 mmol).The colorless solution turned into a white suspension. The reactionmixture was stirred at 0° C. for 2 hours. Ether (50 ml) was added to thewhite suspension and the precipitates were removed by filtration. Theresidue was washed twice with 10 ml of ether. The combined filtrate andwashings were concentrated on a rotary evaporator. The residue oil waschromatographed on silica gel with 50% EtOAc in hexanes to give 1.06 gof Intermediate 2 (4-methanesulfonyloxy-piperidine-1-carboxylic acidtert-butyl ester) as a white solid. MS (APCI): 224 (100%), 180 (32%).

A mixture of Intermediate 1 (0.41 g, 1.80 mmol), Intermediate 2 (0.53 g,1.90 mmol) and sodium hydride (60% dispersion in mineral oil, 0.099 g,2.48 mmol) in 13 ml of anhydrous DMF (dimethylformamide) was stirred at100° C. for 7 hours. After cooling to room temperature, saturated NH₄Clsolution (40 ml) and water (15 ml) were added to quench the reaction.The mixture was extracted three times with 50 ml of ether. The combinedextracts were dried over MgSO₄ and then concentrated on a rotaryevaporator. The residue oil was chromatographed on silica gel with 20%EtOAc in hexanes to give 0.52 g of Intermediate 3(4-[1-(2-fluoro-phenyl)-1H-indazol-3-yloxy]-piperidine-1-carboxylic acidtert-butyl ester) as a pale yellow oil. MS (APCI): 412 (M+1, 62%), 356(46%), 312 (100%).

To a solution of Intermediate 3 (0.52 g, 1.26 mmol) in 4 ml of EtOAc atroom temperature was added 4 ml of a 4 M solution of HCl in dioxane. Thereaction mixture was stirred at room temperature for 3 hours. Thereaction mixture was concentrated on a rotary evaporator. EtOAc (30 ml)was added to dissolve the oily residue. The solution was concentratedagain on a rotary evaporator to remove the last trace of dioxane.Methanol (3 ml) was added to re-dissolve the oily residue. Ether (30 ml)was added slowly to the solution. The cloudy solution was concentratedon a rotary evaporator to give solid material. The solid was trituratedwith 5 ml of 1:1 EtOAc in ether for 15 minutes. An additional 20 ml ofether was added and the precipitates were collected by filtration. Afterwashing twice with 5 ml of ether, the solid was dried at 95° C. undervacuum overnight to give 0.36 g of the title product as a white powder.

Example 2(S)-(+)-1-(2-fluorophenyl)-3-(morpholin-2-ylmethoxy)-1H-indazole maleate

(S)-3-Hydroxymethylmorpholine was prepared according to the proceduredescribed in J. Med. Chem. 1998, 41, 1934-1942. Intermediate 5((S)-2-Hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester) wasprepared under standard conditions (NaOH, di-tert-butyl dicarbonate,H₂O/THF, 0° C.). MP=67-68° C.

Intermediate 6 (2-methanesulfonyloxymethyl-morpholine-4-carboxylic acidtert-butyl ester) was prepared according to the procedure describedabove for the preparation of Intermediate 2 using Intermediate 5 as thestarting material. [α]_(D) ²⁴=+18.4° (CHCl₃, c=8.9), MS (APCI): 240(95%), 196 (100%).

Intermediate 7((S)-2-[1-(2-fluoro-phenyl)-1H-indazol-3-yloxymethyl]-morpholine-4-carboxylicacid tert-butyl ester) was prepared according to the procedure describedabove for the preparation of Intermediate 3 using Intermediate 6 as thestarting material and stirred at 100° C. for 3.5 hours. [α]_(D)²⁴=+16.0° (CHCl₃, c=5.0), MS (APCI): 410 (M+H, 80%), 310 (100%).

To a solution of the Intermediate 7 (0.86 g, 2.00 mmol) in 6 ml of EtOAcwas added 6 ml of a 4 M solution of HCl in dioxane at room temperature.The reaction mixture was stirred at room temperature for 2.5 hours. Thereaction mixture was concentrated on a rotary evaporator. The residuewas loaded onto a 5% HOAc in MeOH solution pre-washed Varian Mega BondElut SCX column. The column was washed four times with 50 ml of MeOH toremove HCl. The amine was eluted out with 1N NH₃ in MeOH solution (3×40ml) to give 0.52 g of the free base as a colorless oil. The oil was thendissolved in 75 ml of ether. A solution of maleic acid (0.187 g, 1.61mmol) in 2 ml of MeOH was added slowly into the amine solution at roomtemperature. A white precipitate was formed and the suspension wasstirred at room temperature for 10 minutes. The white solid wascollected by filtration. It was washed twice with 10 ml of ether andthen dried in vacuum overnight at 100° C. to give 0.661 g of the titleproduct as a white powder.

Example 3(S)-(+)1-(2,4difluorophenyl)-3-(morpholin-2-ylmethoxy)-1H-indazolemaleate

To a slurry of 2,4-difluorophenyl hydrazine hydrochloride (15.2 g) in140 ml of EtOH at room temperature was added 15.64 ml ofdi-isopropylethylamine. The mixture was stirred for 20 minutes untilalmost all was in solution, then isatoic anhydride (14.0 g) was added.The mixture was heated to reflux at which point a solution formed. After1.5 hours, the reaction was cooled to room temperature and let standovernight. The solid that precipitated was filtered off, washed withEtOH, and dried to give 9.36 g (44% yield) of 2-amino-benzoic acidN′-(2,4-difluoro-phenyl)-hydrazide (Intermediate 17): MS (APCI):(M+1)=264, (M−1)=262.

Intermediate 17 (9.80 g, 37.3 mmol) was stirred in 82 ml of 1M HCl (aq),cooled to 0° C. and a solution of sodium nitrite (5.1 g, 74 mmol) in 18ml of water was added cautiously via pipet. A thick suspension formed.106 ml of EtOH was added and the reaction was heated to reflux. A thickfoam formed which was not stirring. The reaction was cooled to roomtemperature, diluted with 100 ml of 1:1 EtOH:H₂O, good stirring wasresumed, and the mixture was heated to reflux for 2 hours. The reactionwas cooled to room temperature overnight, the precipitate was filteredoff, washed with H₂O and dried in the Buchner funnel to give 7.55 g of aputty colored solid, 1-(2,4-difluoro-phenyl)-1H-indazol-3-ol(Intermediate 18) as the product: MS (APCI): (M+1)=247.

Intermediate 19(2-[1-(2,4-difluoro-phenyl)-1H-indazol-3-yloxymethyl]-morpholine-4-carboxylicacid tert-butyl ester) was prepared according to the procedure describedabove for the preparation of Intermediate 3 using Intermediate 6 andIntermediate 18 as the starting materials and stirred at 100° C. for 3hours. [α]_(D) ²⁴=+19.4° (CHCl₃, c=5.4), MS (APCI): 446 (M+H, 100%), 346(90%).

The title product was prepared from Intermediate 19 according to theprocedure described above for the preparation of Example 2.

Examples 4-13 were synthesized in a manner similar to that described forExample 1.

Example 14 (R)-1-phenyl-3-(pyrrolidin-3-ylmethoxy)-1H-indazolehydrochloride

To a slurry of isatoic anhydride (50.0 g, 308.3 mmol) in 514 ml EtOH,was added phenylhydrazine (30.33 ml, 308.3 mmol) and the slurry washeated to reflux. Upon reflux, all of the solid went into solution andthe refluxing was continued for 1.5 hours. The reaction solution wasallowed to cool to room temperature and stand overnight. The solid thatprecipitated was filtered off and washed with EtOH to give 46.55 g (66%yield) of a white solid as the desired hydrazide. The hydrazide (46.55g, 204.8 mmol) was slurried into 442.3 ml 1M HCl solution. The slurrywas cooled to 0° C. and sodium nitrite (28.26 g, 409.6 mmol) in 100 mlwater was added. Next 582 ml EtOH was added and the slurry was heated toreflux for 2 hours, then cooled to room temperature and allowed to standovernight. The resulting slurry was filtered to give 15 g of yellowsolid. The filtrate volume was reduced and more solid was recovered. Thesolids were combined and recrystallized from 95:5 EtOH:iPrOH to afford26.50 g (61%) of light yellow solid as Intermediate 28(1-phenyl-1H-indazol-3-ol): MP=209-211° C.

Intermediate 29((R)-3-(1-phenyl-1H-indazol-3-yloxymethyl)-pyrrolidine-1-carboxylic acidtert-butyl ester) was prepared following the procedure described abovefor the preparation of Intermediate 3 using Intermediate 28 (0.250 g,1.19 mmol) and (R)-3-methanesulfonyloxymethyl-pyrrolidine-1-carboxylicacid tert-butyl ester (0.370 g, 1.30 mmol, prepared according to J. Med.Chem. 1999, 42, 677) as the starting materials and 1.70 mmol of 95% NaH,heating at 100° C. for 18 hours, then adding 1.70 mmol of 60% NaH andheating at 100° C. for 20 hours. The residue oil was chromatographed onsilica gel with 10% acetone in hexanes to give 0.275 g of Intermediate29 as a clear oil.

MS(M+1)=394, 294 (M-BOC).

Intermediate 29 (0.275 g, 0.699 mmol) was dissolved in 2.3 ml EtOAc and2.3 ml HCl (4M in dioxane) was added at room temperature. After stirringovernight, the solvent was evaporated. The residue was treated with ˜30ml of EtOAc and then concentrated. This was repeated to remove all thedioxane and HCl. The resultant white solid was triturated with ˜20 ml of1:2 EtOAc:ether, filtered, washed twice with 5 ml of ml of ether anddried in a vacuum oven at 60° C. overnight to afford the title productas a light tan powder (0.192 g, 83% yield):

Examples 15-26 were synthesized in a manner similar to that describedfor Example 14.

Example 27 1-(2,5-difluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazolehydrochloride

Intermediate 33 (1-(2,5-Difluoro-phenyl)-1H-indazol-3-ol) was preparedaccording to the procedure above for the preparation of Intermediate 28using 2,5-difluorophenyl hydrazine (15.1 g, 105 mmol) and isatoicanhydride (17.0 g, 101 mmol) as starting materials and heating thereaction at reflux for 3.5 hours. The hydrazide was isolated as a lightsand colored solid (15.6 g, 59% yield): MS (APCI): (M+1)=264, (M−1)=262.Following the same procedure, the hydrazide (15.6 g, 59.3 mmol) wasconverted to the Intermediate 33 (12.89 g, 88% yield) as a putty coloredsolid: MS (APCI): (M+1)=247, (M−1)=245.

To a solution of Intermediate 33 (0.300 g, 1.22 mmol) in 12 ml DMF wasadded 0.600 g (1.80 mmol) of cesium carbonate followed by theIntermediate 2 (0.370 g, 1.30 mmol). The mixture was heated to 80° C.for 24 hours and then cooled to room temperature. The reaction wasquenched with saturated NH₄Cl and some extra H₂O, then extracted 3 timeswith Et₂O. The extracts were washed once with H₂O, then once with brine,dried over MgSO₄, and concentrated to 0.515 g yellow oil. The productwas purified by flash chromatography (5-10% EtOAc/Hexanes, 90 g silica)to isolate Intermediate 34(4-[1-(2,5-difluoro-phenyl)-1H-indazol-3-yloxy]-piperidine-1-carboxylicacid tert-butyl ester) as a yellow oil (0.340 g, 65% yield): MS(M+1)=430 (minor), 330 (M-BOC).

Intermediate 34 (0.334 g, 0.778 mmol) was treated with HCl indioxane/EtOAc according to the procedure for Intermediate 30, withstirring at room temperature for 3.5 hours. After the usual work-up, thesolid was triturated with 20 ml of 1:1 EtOAc:ether, filtered, washedtwice with 5 ml of ml of ether and dried in a vacuum oven at 60° C. toafford the title product as a white powder (0.240 g, 84% yield): MS(APCI): (M+1)=330.

Examples 28-40 were synthesized in a manner similar to that describedfor Example 27.

Example 41 1-(4-chloro-phenyl)-3-(piperidin-4-yloxy)-1H-indazolehydrochloride

4-Chlorophenylhydrazine hydrochloride (2.105 g, 14.76 mmol) wassuspended in EtOH (25 ml), treated with di-isopropylethylamine (2.253ml, 12.93 mmol) and stirred for 30 minutes. Isatoic anhydride (1.918 g,11.76 mmol) was added and the mixture was heated to reflux for 3 hours.The reaction mixture was cooled to room temperature and stirredovernight. The material was concentrated to dryness and the resultingresidue was partitioned between EtOAc (˜25 ml) and 50% saturated NaCl(3×30 ml). The organic layer (also containing a small amount of emulsionwhich would not dissipate over 3 extractions) was dried over MgSO₄ andconcentrated to an orange solid. The material was triturated with EtOAc,filtered and rinsed with additional EtOAc. The filtrate was concentratedto dryness and treated with DCM (dichloromethane). The mixture wasstirred overnight. The mixture was filtered, rinsed with DCM and thesolid dried to provide 1.538 g (50%) of 2-amino-benzoic acidN′-(4-chloro-phenyl)-hydrazide (Intermediate 40) as a mauve-coloredsolid. MS (APCI): (M+1)=262.1, (M−1)=260.0.

Intermediate 40 (1.538 g, 5.877 mmol) was suspended in 1M HCl (12 ml),cooled to 0° C. and treated dropwise with a solution of sodium nitrite(811 mg, 11.75 mmol) in water (5 ml). The mixture was stirred for 10minutes at 0° C., diluted with 1:1 EtOH/H₂O (25 ml), heated to refluxfor 3 hours, then cooled to room temperature and stirred for about 1hour. The mixture was filtered and rinsed with water. The isolated solidwas treated with Et₂O and EtOAc, followed by 1N NaOH. A large amount ofsolid remained that would not dissolve. The mixture was poured into aseparatory funnel and allowed to separate. All of the solid partitionedinto the organic layer, so the aqueous layer was drained (designatedaqueous layer 1). The organic layer was then treated with additional 1NNaOH. The solid then partitioned into the aqueous layer and this too wasdrained (with solid—designated aqueous layer 2). Both of the aqueouslayers were treated with concentrated HCl until approximately neutral.Aqueous layer 1 formed a nice solid that was filtered, rinsed with waterand dried. The solid was dried in a vacuum oven at 50° C. for 2 days toafford 141 mg (9.8%) of 1-(4-chloro-phenyl)-1H-indazol-3-ol(Intermediate 41) as a tan solid. Aqueous layer 2, however, formed largeclumps of emulsion-looking solids. This material was allowed to stand atroom temperature for 2 days then stirred vigorously until all of theclumps broke up. Ethyl acetate was then added, the mixture was madebasic with 1 N NaOH, and the solid was filtered and washed with EtOAc.The solid was dried in a vacuum oven at 50° C. over three days to afford522 mg (36%) of Intermediate 41 as a white solid. MS (APCI):(M+1)=245.1, (M−1)=243.0.

Intermediate 41 (300 mg, 1.226 mmol) was combined with dry DMF (10 ml),treated with PS-BEMP resin(2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro1,3,2-diazaphosphorineon polystyrene), (1.115 g) and stirred for 30 minutes. A solution ofIntermediate 2 (377 mg, 1.349 mmol) in dry DMF (5 ml) was added slowlydropwise, and the mixture was heated to 70° C. overnight. The mixturewas filtered to remove the resin, and the resin was washed with hot DMF.The filtrate was concentrated in vacuo. The crude material waschromatographed over 20 g silica gel, eluting with 8% EtOAc/Hexanes. Theappropriate fractions were combined and concentrated to afford 212 mg(40%) of4-[1-(4-chloro-phenyl)-1H-indazol-3-yloxy]-piperidine-1-carboxylic acidtert-butyl ester (Intermediate 42) as a colorless glass. MS (APCI):(M−1)=426.2.

Intermediate 42 (212 mg, 0.495 mmol) was dissolved in EtOAc (2 ml),treated with 4M HCl in dioxane (1.61 ml, 6.44 mmol) and stirredovernight at room temperature. The mixture was concentrated in vacuo,treated with EtOAc and concentrated again. This process was repeated 5times. The resulting white solid was triturated with Et₂O, filtered,rinsed with Et₂O and dried in a vacuum oven at 50° C. to afford 155 mg(86%) of the titleproduct—1-(4-chloro-phenyl)-3-(piperidin-4-yloxy)-1H-indazolehydrochloride as a white solid.

Examples 42-43 were synthesized in a manner similar to that describedfor Example 41, except di-isopropylethylamine was replaced withtriethylamine and ethanol was replaced with tetrahydrofuran (THF).

Example 44 (S)-(−)-3-(piperidin-3-ylmethoxy)-1-pyridin-2-yl-1H-indazolemaleate

A mixture of isatoic anhydride (3.51 g, 2.15 mmol) and2-hydrazinopyridine (2.40 g, 2.20 mmol) in 35 ml of EtOH was refluxedfor 17 hours. After refluxing for 15 minutes, the suspension turned intoa brown solution and gas evolution was observed. At the end of the 17hour period, the reaction mixture was cooled to room temperature and thebrown solution was concentrated on a rotary evaporator. The residue waschromatographed on silica gel with 65% EtOAc in hexanes. The fractionscontaining the product were collected and concentrated. The solid wastriturated with ether (100 ml) for 15 minutes and collected byfiltration. It was air-dried to give 2.68 g of 2-amino-benzoic acidN′-pyridin-2-yl-hydrazide (Intermediate 9) as a white solid. MS (APCI):229 (M+1, 100%).

To a solution of Intermediate 9 (1.38 g, 6.04 mmol) in 21 ml of 1M HClsolution at 0° C. was added a solution of sodium nitrite (0.90 g, 1.31mmol) in 5 ml water. A white precipitate was obtained on addition of thesodium nitrite solution. EtOH (30 ml) was then added and the mixture wasrefluxed for 2 hours. The white suspension turned into a yellow solutionduring reflux. After 2 hours, the mixture was cooled to roomtemperature. The orange color solution turned into an orange colorsuspension. The mixture was concentrated on a rotary evaporator. Thesolid residue was dissolved in a mixture of EtOAc (70 ml), THF (30 ml),saturated NaHCO₃ solution (80 ml) and water (40 ml). The mixture wasstirred at room temperature for 15 minutes. The organic layer wascollected and the aqueous layer was extracted twice with 70 ml of EtOAc.The combined organic layers were dried over MgSO₄ and concentrated togive 1.05 g of 1-pyridin-2-yl-1H-indazol-3-ol (Intermediate 10) as apale yellow solid. MS (APCI): 212 (M+1, 100%).

Intermediate 11 ((S)-3-methanesulfonyloxymethyl-piperidine-1-carboxylicacid tert-butyl ester) was prepared according to the procedure describedabove for the preparation of Intermediate 2 using(S)-3-hydroxymethyl-1-N-Boc-piperidine (Astatech) as the startingmaterial. (Boc=tert-butyloxycarbonyl). [α]_(D) ²⁴=+18.8° (CHCl₃, c=4.9),MS (APCI): 238 (100%), 194 (73%).

Intermediate 12((S)-3-(1-pyridin-2-yl-1H-indazol-3-yloxymethyl)-piperidine-1-carboxylicacid tert-butyl ester) was prepared according to the procedure describedabove for the preparation of Intermediate 3 using Intermediate 11 andIntermediate 10 as the starting materials and stirred at 100° C. for 1.5hours. [α]_(D) ²⁴=+21.8° (CHCl₃, c=5.5), MS (APCI): 409 (M+H, 100%), 309(100%).

The title product was prepared from Intermediate 12 according to theprocedure described above for the preparation of Example 2.

Example 45(S)-(−)-5-fluoro-1-(2-fluorophenyl)-3-(piperidin-3-ylmethoxy)-1H-indazolemaleate

To a solution of 2-amino-5-fluorobenzoic acid (15.34 g, 98.86 mmol) andsodium carbonate (10.66 g, 100.6 mmol) in 260 ml of water at roomtemperature was added a 1.93 M phosgene solution in toluene (63 ml,121.6 mmol) slowly with vigorous stirring. A yellow precipitate wasformed during the addition. The mixture was stirred at room temperaturefor 30 minutes after the addition of phosgene was completed. Theprecipitate was collected by filtration and washed four times with 100ml of water. The solid was air-dried for 30 minutes then it was washedwith a 1:1 mixture of ether in hexanes (3×40 ml). The solid was againair-dried to give 17.36 g of Intermediate 21(6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.16 (dd, J=8.78, 3.90 Hz, 1H) 7.62 (dd,J=8.66, 3.29 Hz, 1H) 7.66 (m, 1H) 11.75 (s, 1H).

A mixture of Intermediate 21 (8.42 g, 46.48 mmol) and2-fluorophenylhydrazine (6.00 g, 47.57 mmol) in 100 ml of anhydrous THFwas refluxed for 4 hours. The reaction mixture turned gradually from ayellow suspension into an orange colored solution. At the end of the4-hour period, the reaction mixture was cooled to room temperature andthe mixture was concentrated on a rotary evaporator. The residue wastriturated with a 1:1 mixture of ether in hexanes (2×15 ml) for 15minutes and the solid was collected by filtration. It was air-dried togive 7.62 g of Intermediate 22 (2-amino-5-fluoro-benzoic acidN′-(2-fluoro-phenyl)-hydrazide) as a white solid. MS (APCI): 264 (M+1,100%).

To a suspension of Intermediate 22 (7.61 g, 28.92 mmol) in 65 ml of a 1MHCl solution at 0° C. was added a solution of sodium nitrite (4.20 g,60.93 mmol) in 17 ml of water. Next EtOH (95 ml) was added and theslurry was refluxed for 2 hours. The reaction mixture was cooled to roomtemperature and then concentrated on a rotary evaporator. Saturated NaClsolution (40 ml), water (30 ml), EtOAc (150 ml) and THF (100 ml) wereadded to dissolve the solid material. The organic layer was collectedand the aqueous layer was extracted with EtOAc (100 ml). The combinedorganic layers were dried over MgSO₄ and then concentrated on a rotaryevaporator. The residue was triturated with ether (40 ml) and the solidwas collected by filtration. The solid was washed again with a 1:1mixture of ether in hexanes (2×10 ml) and air-dried to give 5.66 g ofIntermediate 23 (5-fluoro-1-(2-fluoro-phenyl)-1H-indazol-3-ol) as anoff-white powder. MS (APCI): 247 (M+1, 100%), 248 (27%).

Intermediate 24((S)-3-[5-fluoro-1-(2-fluoro-phenyl)-1H-indazol-3-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester) was prepared according to the procedure describedabove for the preparation of Intermediate 3 using Intermediate 11 andIntermediate 23 as the starting materials and stirred at 100° C. for 4hours.

The title product was prepared from the Intermediate 24 according to theprocedure described above for the preparation of Example 2.

Example 46(S)-(+)-5-fluoro-1-(2-fluorophenyl)-3-(morpholin-2-ylmethoxy)-1H-indazolemaleate

Intermediate 26((S)-2-[5-fluoro-1-(2-fluoro-phenyl)-1H-indazol-3-yloxymethyl]-morpholine-4-carboxylicacid tert-butyl ester) was prepared according to the procedure describedabove for the preparation of Intermediate 3 using Intermediate 6 andIntermediate 23 as the starting materials and stirred at 100° C. for 3hours. [α]_(D) ²⁴=+18.2° (CHCl₃, c=5.1), MS (APCI): 446 (M+H, 86%), 447(22%), 390 (21%), 346 (100%), 347 (20%).

The title product was prepared from Intermediate 26 according to theprocedure described above for the preparation of Example 2.

Examples 47-49 were synthesized in a manner similar to that describedfor Example 45.

Example 50 was synthesized in a manner similar to that described forExample 45, except CDI (1,1′-Carbonyldiimidazole) was used in place ofphosgene.

Example 515-fluoro-1-(2-fluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazolehydrochloride

Intermediate 23 (1.00 g, 4.10 mmol) was dissolved in 41 ml CH₃CN and 10ml DMF. To the solution at 50° C. was added 2.0 g of cesium carbonate(6.10 mmol). After 10 minutes, Intermediate 2 (1.14 g, 4.06 mmol) wasadded and the mixture was heated to 80° C. After 22 hours, the reactionwas cooled to room temperature, quenched with saturated NH₄Cl and someextra H₂O, then extracted three times with Et₂O. The extracts werewashed once with H₂O, then once with brine, dried over MgSO₄, andconcentrated to 2.61 g yellow oil. The crude product was purified byflash chromatography (1×10-20% EtOAc/hexanes, 1×10% EtOAc/hexanes) toisolate Intermediate 31(4-[5-fluoro-1-(2-fluoro-phenyl)-1H-indazol-3-yloxy]-piperidine-1-carboxylicacid tert-butyl ester) as a yellow oil (1.13 g, 65%): MS (APCI):(M+1)=430, 330 (M-BOC).

Intermediate 31 (1.13 g, 2.63 mmol) was treated with HCl indioxane/EtOAc according to the procedure for Example 14, with stirringat room temperature overnight. After the usual work-up, the solid wastriturated with 40 ml Et₂O, filtered, and washed with 2 more portions ofEt₂O to give the title product as a white solid (0.721 g, 75% yield):MS(M+1)=330.

Examples 56-57 were synthesized in a manner similar to that describedfor Example 51.

Example 525-fluoro-1-(2-fluoro-phenyl)-3-(1-methyl-piperidin-3-ylmethoxy)-1H-indazolehydrogen chloride

To a room temperature solution of piperidine-1,3-dicarboxylicacid-1-tert-butyl ester (5.00 g, 21.81 mmol) in 20% MeOH/toluene (100ml) was added 14.18 ml of (trimethylsilyl)diazomethane (2.0 M, 28.35mmol) dropwise and the reaction was monitored by TLC until completionand then concentrated under reduced pressure to yield 4.44 g (83.7%) ofpiperidine-1,3-dicarboxylic acid 1-tert-butyl ester-3-methyl ester(Intermediate 53). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.4 (s, 9H), 1.6 (d,J=3.4 Hz, 1H), 1.6 (m, 1H), 1.7 (m, 1H), 2.0 (m, 1H), 2.4 (m, 1H), 2.8(m, 1H), 3.0 (s, 1 H), 3.7 (s, 3H), 3.9 (d, J=13.2 Hz, 1H), 4.1 (s, 1H).

To a −78 ° C. stirred solution of Intermediate 53 (2.22 g, 9.13 mmol) indry THF (30 ml) was added NaHMDS (sodium hexamethyldisilazane) (1.0 M inTHF, 10.03 mmol) dropwise. The reaction was stirred at this temperaturefor 30 minutes and then iodomethane (0.682 ml, 10.95 mmol) was addeddropwise. The reaction was allowed to warm to room temperature overnightwith good stirring. The reaction was cooled and then quenched withsaturated NH₄Cl. The layers were separated and the aqueous layer wasextracted three times with 20 ml of EtOAc and the organic extracts werecombined. The organic phase was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The oil was purified by silicachromatography using hexanes/EtOAc (0→15%) to yield 2.25 g (95.8%) of3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methylester (Intermediate 54). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.0 (s, 3H), 1.3(s, 9H), 1.4 (m, 2H), 1.9 (m, 2H), 3.0 (d, J=13.2 Hz, 1H), 3.1 (m, 1H),3.3 (m, 1H), 3.5 (s, 3H), 3.7 (d, J=13.4 Hz, 1H).

To a 0° C. stirred solution of Intermediate 54 (1.17 g, 4.56 mmol) indry THF (20 ml) was added LiAlH₄ (1.0 M in THF, 9.11 ml, 9.11 mmol)dropwise and the reaction was allowed to warm to room temperature. Uponcompletion as indicated by TLC, the reaction was carefully quenched withsaturated NH₄Cl and EtOAc was added. The layers were separated, theaqueous layer was extracted with EtOAc (3×15 ml) and the organicextracts were combined. The organic phase was dried over Na₂SO₄,filtered and concentrated under reduced pressure to yield 0.844 g(42.1%) of 3-hydroxymethyl-3-methyl-piperidine-1-carboxylic acidtert-butyl ester (Intermediate 55). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.9(s, 3H), 1.3 (m, 2H), 1.5 (s, 9H), 1.5 (m, 3H), 2.9 (s, 1H), 3.1 (s,1H), 3.5 (d, J=11.5 Hz, 1H), 3.8 (m, 2H).

To a 0° C. stirred solution of Intermediate 55 (0.844 g, 3.68 mmol) indry CH₂Cl₂ (25 ml) was added Et₃N (0.513 ml, 3.682 mmol) and thereaction was stirred for 15 minutes. Methansulfonyl chloride (0.285 ml,3.682 mmol) was added dropwise and the reaction was allowed to warm toroom temperature overnight with good stirring. The reaction was completeby TLC, and Et₂O (100 ml) was added. The mixture was filtered and thefilter caked was washed with additional Et₂O. The filtrate was thenconcentrated under reduced pressure. The residue was chromatographedwith hexanes/EtOAc (0→25%) to yield 1.05 g (93.1%) of3-methanesulfonylmethyl-3-methyl-piperidine-1-carboxylic acid tert-butylester (Intermediate 56). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.0 (s, 3H), 1.4(m, 1H), 1.4 (s, 9H), 1.6 (m, 3H), 3.0 (s, 3H), 3.2 (s, 1H), 3.5 (s,2H), 4.0 (d, J=2.4 Hz, 2H).

To Intermediate 23 (0.300 g, 1.22 mmol) in dry DMF (10 ml) was addedCs₂CO₃ (0.596 g, 1.83 mmol) and the mixture was stirred for 30 minutes.Intermediate 56 (0.412 g, 1.34 mmol) was added and the reaction washeated to 80° C. overnight with good stirring. The reaction was notcomplete by HPLC (81% conversion), however, the heat was turned off andthe reaction was allowed to cool to room temperature. The reaction wasquenched with saturated NH₄Cl followed by addition of small amount ofH₂O and then poured into Et₂O. The layers were separated and the aqueousphase was extracted with Et₂O (3×15 ml). The organic extracts werecombined, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The oil was purified by silica chromatography usinghexanes/EtOAc (0→10%) to yield 0.127 g (22.8%) of3-[5-fluoro-1-(2-fluoro-phenyl)-1H-indazol-3-yloxymethyl]-3-methyl-piperidine-1-carboxylicacid tert-butyl ester (Intermediate 57). MS (APCI): (M+1)=458. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.1 (s, 3H), 1.4 (s, 9H), 1.5 (m, 1H) 1.6 (m,2H), 1.7 (m, 1H), 3.3 (s, 1H), 3.5 (m, 3H), 4.2 (d, J=30.0 Hz, 2H), 7.2(m, 2H), 7.3 (s, 1H), 7.3 (s, 1H), 7.3 (m, 2H), 7.6 (m, 1H).

To a room temperature stirred solution of Intermediate 57 (0.127 g,0.278 mmol) in EtOAc (0.925 ml) was added 0.902 ml of a 4.0 M HClsolution in dioxane. The reaction was allowed to stir overnight at roomtemperature. Upon completion as indicated by HPLC, the reaction wasconcentrated under reduced pressure. EtOAc was added to the solid andthen concentrated down under reduced pressure. This process was repeatedfive times. The solid was triturated with EtOAc/Et₂O (2:1), the solidwas filtered and then washed with Et₂O (2×15 ml). The solid was placedin a drying oven under reduced pressure to yield 0.089 g (81.7%) of thetitle product.

Example 531-(2-fluoro-phenyl)-3-(3-methyl-piperidin-3-ylmethoxy)-1H-indazolehydrogen chloride

The title product was synthesized in the same manner as Example 52 fromIntermediate 1 to yield 0.121 g (76.1%) of product.

Example 545-fluoro-1-(2-fluoro-phenyl)-3-(4-methyl-piperdin-4-ylmethoxy)-1H-indazolehydrogen chloride

The compound was synthesized in the same manner as Example 52 from5-fluoro-1-(2-fluoro-phenyl)-1H-indazol-3-ol (Intermediate 23) and4-methanesulfonyloxymethyl-4-methyl-piperidine-1-carboxylic acidtert-butyl ester, synthesized from piperidine-1,4-dicarboxylic acidmono-tert-butyl ester in the same manner as Intermediate 56, to yield0.068 g (50.3%) of the title product.

Example 55(R)-5-fluoro-1-(2-fluoro-phenyl)-3-(piperidin-3-ylmethoxy)-1H-indazolemaleate

3-[5-fluoro-1-(2-fluoro-phenyl)-1H-indazol-3-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester was prepared according to the procedure forIntermediate 57 from Intermediate 23 (0.500 g, 2.03 mmol) and(R)-3-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butylester (0.655 g, 2.23 mmol). A room temperature stirred solution ofcarbamate in EtOAc (5.43 ml) was treated with 5.30 ml of a 4.0 M HClsolution in dioxane. The reaction was allowed to stir overnight at roomtemperature and was concentrated under reduced pressure, triturated withEtOAc and again concentrated under reduced pressure. This process wasrepeated three times. Recrystallization of the foam was attempted fromhexanes/EtOAc and acetone/hexanes without success. The free base wasformed by adding Dowex 550A (OH) Anion Exchange Resin to a stirredsolution of the salt in MeOH (10 ml). The mixture was stirred for 30minutes, filtered and the beads washed three times with 20 of methanol.The organic phase was concentrated under reduced pressure to yield0.3628 g of the free base as a yellow oil. To a stirred solution of theoil in EtOAc (10 ml) was added maleic acid (0.111 g, 1.0 equivalents). Asolid precipitated out and the mixture was concentrated under reducedpressure. The solid was triturated with hexanes/Et₂O, filtered andwashed with Et₂O. The white solid was dried in the oven under reducedpressure at 80° C. overnight to yield 0.390 g (69.6%) of the titlemaleate salt.

Example 585-chloro-1-(2,5-difluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazolehydrochloride

A solution of 2-amino-5-chloro-benzoic acid (3.0 g, 17.0 mmol) and(2,5-difluoro-phenyl)-hydrazine hydrochloride (3.2 g, 17.5 mmol) in dryTHF (tetrahydrofuran) (20 ml) was treated with HOBT(1-hydroxybenzotriazole hydrate) (5.4 g, 35.0 mmol). The resultingmixture was cooled to about −12° C. N-Me-morpholine (3.7 g, 36.7 mmol)was added and the mixture was stirred for 5 minutes before addingEDAC-HCl (1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride)(3.4 g, 17.5 mmol). The mixture was stirred at −12° C. for 1 hour andthen allowed to warm to room temperature and stirred overnight. Thereaction was partitioned between EtOAc (50 ml) and water (50 ml). Thelayers were separated and the organic layer was washed four times withsaturated aqueous NaCl, dried over MgSO₄, and concentrated in vacuum.The resulting solid was triturated with ether, filtered and dried in thevacuum oven overnight at 70° C. and 15 mm Hg to provide Intermediate 36(2-amino-5-chloro-benzoic acid N′-(2,5-difluoro-phenyl)-hydrazide) (4.0g, 77% yield) as a light yellow solid: MS (APCI): (M+1)=298.0

To a 0° C. solution of Intermediate 36 (3.9 g, 13.0 mmol) in 1M HCl (35ml) was added slowly a solution of NaNO₂ in 10 ml water. The resultingmixture was stirred 10 minutes before diluting with 1:1 EtOH/H₂O (50ml). The mixture was heated to reflux for 3 hours, cooled to roomtemperature and let stir 1 hour. The solid was filtered off, washedtwice with 20 ml of water, and dried in the vacuum oven overnight at 70°C. (15 mm Hg) to afford Intermediate 37(5-chloro-1-(2,5-difluoro-phenyl)-1H-indazol-3-ol) (3.7 g, 95% yield) asa brown solid: MS (APCI): (M+1)=281.0.

Intermediate 38 was prepared according to the procedure for Intermediate34 described above using Intermediate 37 (0.5 g, 1.8 mmol), andIntermediate 2 as starting materials to obtain the desired product,Intermediate 38(4-[5-chloro-1-(2,5-difluoro-phenyl)-1H-indazol-3-yloxy]-piperidine-1-carboxylicacid tert-butyl ester) (0.48 g, 58% yield): MS (APCI): (M+1)=464.0.

Intermediate 39 was prepared according to the procedure for Example 14described above using Intermediate 38 (0.45 g, 0.97 mmol), as thestarting material to obtain desired title product5-chloro-3-cyclohexyloxy-1-(2,5-difluoro-phenyl)-1H-indazolehydrochloride (0.35 g, 90% yield.

Examples 59-95 were synthesized in a manner similar to that describedfor Example 58 using the appropriate 2-amino-benzoic acid. Examples96-97 were synthesized in a manner similar to that described for Example58, except CH₃CN/DMF was used in place of DMF in the reaction of theindazol-3-ol with Cs₂CO₃. Example 98 was synthesized in a manner similarto that described for Example 58, except Cs₂CO₃ was replaced by NaH.Example 99 was synthesized in a manner similar to that described forExample 58, except pyridylhydrazine was used instead of phenylhydrazine.

Example 1004-fluoro-1-(2-fluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazolehydrochloride

2-Amino-6-fluorobenzoic acid (2.00 g, 12.89 mmol) was combined with2-fluorophenylhydrazine hydrochloride (2.096 g, 12.89 mmol) and HOBt(3.949 g, 25.79 mmol) in dry THF (75 ml) and cooled to about −12° C.N-Methylmorpholine (2.835 ml, 25.79 mmol) was added, the mixture wasstirred for 5 minutes, then EDC hydrochloride (2.66 g, 13.88 mmol) wasadded. The mixture was maintained at a temperature between −14 and −10°C. for 1 hour, then allowed to slowly warm to room temperature andstirred for 18 hours. The mixture was cooled to 0° C., then filteredthrough CELITE® (diatomaceous earth). The filtrate was diluted withEtOAc, treated with saturated NaHCO₃ and the layers separated. Theorganic layer was washed twice with 50% saturated NaHCO₃ and then driedover MgSO₄ and concentrated. The resulting solid was triturated withdichloromethane, filtered, rinsed with a very small amount ofdichloromethane and dried. The filtrate from the trituration wasre-triturated with a small amount of dichloromethane, filtered, rinsedwith a tiny amount of dichloromethane and dried. The filtrate wasconcentrated to dryness, triturated with a small amount of Et₂O,filtered, rinsed with a tiny amount of ether and dried. The three solidswere combined to afford a total of 2.182 g (64%) of2-amino-6-fluoro-benzoic acid N′-(2-fluoro-phenyl)-hydrazide(Intermediate 44) as an off-white solid. MS (APCI): (M−1)=262.0.

Intermediate 44 (2.182 g, 8.289 mmol) was suspended in 1M HCl (20 ml),cooled to 0° C. and treated dropwise with a solution of sodium nitrite(1.144 g, 16.58 mmol) in water (7 ml). The mixture was stirred for 10minutes at 0° C., diluted with 1:1 EtOH/H₂O (30 ml) and heated to refluxfor 3 hours, then stirred at room temperature for 18 hours. The solidwas filtered, rinsed with water and dried to afford 1.939 g (95%) of4-fluoro-1-(2-fluoro-phenyl)-1H-indazol-3-ol (Intermediate 45) as a tansolid. MS (APCI): (M+1)=247.1, (M−1)=245.0.

4-[4-Fluoro-1-(2-fluoro-phenyl)-1H-indazol-3-yloxy]-piperidine-1-carboxylicacid tert-butyl ester (Intermediate 46) was prepared as described abovefor Intermediate 42 using Intermediate 45 (300 mg, 1.218 mmol), PS-BEMPresin (1.108 g) and 4-methanesulfonyloxy-piperidine-1-carboxylic acidtert-butyl ester (Intermediate 2) (374 mg, 1.34 mmol) in DMF (10 ml) toafford 265 mg (51%) of Intermediate 46 as a yellow oil. MS (M+1)=430.2.

The title product was prepared as described above for Example 41 using(Intermediate 46) (265 mg, 0.617 mmol) and 4 M HCl in dioxane (2.00 ml)in EtOAc (2 ml) to afford 202 mg (89%) as a white solid.

Examples 101-103 were synthesized in a manner similar to that describedfor Example 100.

Example 104(S)-(−)-1-phenyl-3-(piperidin-3-ylmethoxy)-1H-pyrazolo[3,4-b]pyridinehydrochloride

To a solution of 2-chloronicotinoyl chloride (5.05 g, 2.87 mmol) in 50ml of anhydrous methylene chloride at 0° C. was added triethylamine (4.5ml, 3.23 mmol) followed by phenylhydrazine (2.9 ml, 2.95 mmol). Thereaction mixture was concentrated on a rotary evaporator. Water (40 ml)was added and the mixture was extracted three times with 80 ml of EtOAc.The combined organic layers were dried over MgSO₄ and then concentrated.The solid residue was triturated with a 1:1 mixture of EtOAc and hexanes(60 ml). The solid was collected by filtration and then air-dried afterwashing twice with 10 ml of ether. The neat solid was then heated to175° C. for approximately 15 minutes. The solid melted at 175° C. to anorange colored liquid initially and then solidified to give 1.84 g of abrown solid, Intermediate 14 (1-phenyl-1H-pyrazolo[3,4-b]pyridin-3-ol).MS (APCI): 212 (M+1, 100%).

Intermediate 15(3-(1-phenyl-1H-pyrazolo[3,4-b]pyridin-3-yloxymethyl)-piperidine-1-carboxylicacid tert-butyl ester) was prepared according to the procedure describedabove for the preparation of Intermediate 3 using Intermediate 11 andIntermediate 14 as the starting materials and stirred at 100° C. for 1.5hours. [α]_(D) ²⁴=+17.4° (CHCl₃, c=10.8), MS (APCI): 409 (M+H, 60%), 309(100%).

To a solution of Intermediate 15 (0.72 g, 1.75 mmol) in 7 ml of EtOAc atroom temperature was added a 4M HCl solution in dioxane (5 ml, 20.0mmol). The pale yellow solution turned into a bright yellow solution andafter stirring for 5 minutes, a precipitate formed. The mixture wasstirred at room temperature for 2 hours. The solid was collected byfiltration and washed with ether (5×10 ml). The yellow solid was driedovernight under vacuum at 90° C. to give 0.52 g of the titlehydrochloride salt as a white solid.

Example 105 were synthesized in a manner similar to that described forExample 104.

Example 106 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazoleL-tartrate

To a stirred suspension of 2-fluorophenylhydrazine, hydrochloride (100g, 0.614 moles) in ethanol (1.0 L) was added in a stream over a 10minute period at 22-23° C., triethylamine (68.4 g, 0.68 moles). Thesuspension was stirred for 5 minutes and then isatoic anhydride (100 g,0.614 moles) was added. The resulting suspension was stirred attemperatures reaching reflux (78° C.) over the next hour as a solutionformed. The solution was stirred at reflux for 2.5 hours. It was thenstirred at −10° C. for 2 hours and filtered. The solid was rinsed withethyl acetate (100 ml) and pressed dry under suction. The solid wassuspended in water (400 ml) and stirred at room temperature for 0.5hour. The solid was filtered off, washed with water (5×30 ml) andpressed dry under suction. Further drying in vacuo at 33° C. for 17hours afforded 63.3 g (42%) of Intermediate 48 (2-amino-benzoic acidN′-(2-fluoro-phenyl)-hydrazide). The organic filtrate was concentratedin vacuo to dryness. The residue was triturated with water (500 ml, then3×200 ml) and suspended in ethanol:ethyl acetate (1:1, 150 ml). Thesolid was filtered off, rinsed with ethyl acetate (50 ml) and presseddry under suction. Further drying in vacuo at 32° C. for 6 hoursprovided an additional 13.7 g (9%) of product. Total yield=77.0 g (51%).¹H NMR (DMSO-d₆) δ: 10.1 (s, 1H), 7.6 (m, 1H), 7.2 (t, 1H), 7.1 (m, 1H),6.95 (m, 1H), 6.8 (t, 1H), 6.7 (m, 2H), 6.5 (t, 1H), 6.4 (s, 2H).

To a stirred suspension of Intermediate 48 (150 g, 0.257 moles) in 1 NHCl (560 ml) at −3° C. to −2° C. was added dropwise over a 40 minuteperiod, a solution of sodium nitrite (35.5 g, 0.514 moles) in water (175ml). Gas evolution was noted. The foamy suspension was stirred at 0° C.to −5° C. for 0.5 hour. Ethanol (1.05 L) was added and the solution washeated to reflux over a 45-minute period. The suspension was stirred atreflux for 1.5 hours. Ethanol (˜250 ml) was distilled off at atmosphericpressure over the next 45 minutes. The suspension was cooled withstirring to −10° C. for 0.5 hour and filtered. The solid was rinsed fourtimes with 30 ml of isopropanol and pressed dry under suction. Furtherdrying in vacuo at 58° C. for 7 hours afforded 52.5 g (89.5%) ofIntermediate 1 (1-(2-fluoro-phenyl)-1H-indazol-3-ol). ¹H NMR (DMSO-d₆)δ: 7.7 (d, 1H), 7.6 (t, 1H), 7.3-7.5 (m, 4H), 7.2 (m, 1H), 7.1 (t, 1H).

To Intermediate 1 (52 g, 0.228 moles) in dimethylformamide (480 ml) wasadded cesium carbonate (111.5 g, 0.342 moles) with stirring. The mixturewas stirred at room temperature for 0.5 hour. The4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl esterIntermediate 2 (70 g, 0.251 moles) was added and the mixture was stirredat 80-85° C. for 18 hours. The resulting suspension was cooled to 10° C.with an ice-water bath. Saturated aqueous ammonium chloride (250 ml) wasadded in a stream over a 20-minute period. The mixture was poured intostirred ice-water (2 L). The mixture was extracted with ether (1 L, 500ml). The extract was dried over magnesium sulfate and concentrated invacuo to an orange-amber oil (124 g). This oil was dissolved in amixture of hexane:ethyl acetate (1:8, 150 ml). Silica gel (230-400 mesh,150 g) was added to the turbid solution. The slurry was poured onto asilica gel (230-400 mesh, 850 g) pad. The pad was eluted with ethylacetate in hexane (5%→8%). The total volume of solvent used was 21 L.The combined eluates were concentrated in vacuo to 88 g (94%) ofIntermediate 3(4-[1-(2-Fluoro-phenyl)-1H-indazol-3-yloxy]-piperidine-1-carboxylic acidtert-butyl ester) as a pale yellow gum. ¹H NMR (CDCl₃) δ: 7.7 (d, 1H),7.6 (t, 1H), 7.4 (t, 1H), 7.2-7.4 (m, 4H), 7.15 (t, 1H), 5.1 (m,1H), 3.8(m, 2H), 3.4 (m, 2H), 2.1 (m, 2H), 2.05 (s, 3H), 1.9 (m, 2H), 1.5 (s,9H).

To a stirred solution of Intermediate 3 (85 g, 0.207 moles) in ethylacetate (600 ml) at 21° C. was added in a narrow stream over a 35-minuteperiod, 4M HCl in dioxane (600 ml) causing a temperature rise to 24° C.The solution was stirred at 22-23° C. for 3 hours. The solution wasconcentrated in vacuo to a thick oil which began to solidify. Ethylacetate (200 ml) was added and the resulting thick suspension wasstirred at 0° C. for 1 hour. The solid was filtered off, rinsed twicewith 30 ml of ethyl acetate and pressed dry under suction. Furtherdrying in vacuo at 35° C. for 16 hours afforded 66.5 g (93%) of1-(2-fluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazole hydrochloride. ¹HNMR (CD₃OD) δ: 7.7 (d, 1H), 7.6 (t, 1H), 7.5-7.6 (m, 2H), 7.3-7.5 (m,2H), 7.25 (m, 1H), 7.2 (t, 1H), 5.2 (m, 1H), 3.4-3.5 (m, 2H), 3.2-3.3(m, 2H), 2.3-2.4 (m, 2H), 2.2-2.3 (m, 2H). MS (APCI): (M+1)=311.

A mixture of 1-(2-fluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazolehydrochloride (9.0 g, 0.026 moles) in tetrahydrofuran (20 ml) and water(100 ml) was stirred at room temperature for 0.5 hour as a solutionformed. Sodium carbonate (15 g, 0.142 moles) was added portion-wise overa 5-minute period, followed by ether (150 ml). The mixture was shakenand the layers were separated. The aqueous layer was extracted withether (100 ml). The combined organic layers were dried over magnesiumsulfate and concentrated in vacuo to a gum (8.0 g, 99% crude). To thisgum was added, all at once, a solution of L-tartaric acid (4.0 g, 0.0267mol) in water (80 ml). The mixture was stirred for ˜2 minutes when acomplete solution formed. Stirring was continued and after ˜2 minutessolid began precipitating. The suspension was stirred at 0° C. for 3hours and filtered. The solid was rinsed with water (15 ml) and presseddry under suction. Further drying in vacuo at 50° C. for 16 hoursprovided 10.2 g (85.5%) of the L-tartratesalt—1-(2-fluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazole L-tartrate.

Example 107(S)-5-fluoro-1-(2-fluorophenyl)-3-(piperidin-3-ylmethoxy)-1H-indazoleL-tartrate

2-Amino-5-fluoro-benzoic acid (20.0 g, 129 mmol) was dissolved in dryTHF (390 ml). 1,1′-Carbonyldiimidazole (CDI, 22.0 g, 135 mmol) was addedin one portion. Some gas evolution was observed and a very thick beigesolid precipitated out. The suspension was stirred for 1 hour 20 minutesat room temperature. Eventually, the precipitate thinned out.N,N-diisopropylethylamine (DIPEA, 27 ml, 155 mmol) was added, whichcaused the precipitate to fully dissolve, followed by the addition of(2-fluoro-phenyl)-hydrazine hydrochloride (23.1 g, 142 mmol). Themixture was stirred at room temperature for 18 hours. The reaction wascarefully quenched with water (1 L) and ethyl acetate (500 ml) wasadded. The two layers were separated and the aqueous layer was washedtwice with 200 ml of water, then twice with 100 ml of saturated, aqueousNaHCO₃ solution, then with saturated brine, and dried over MgSO₄. Thesolvent was removed to give 32.21 g (95% yield) of Intermediate 22(2-amino-5-fluoro-benzoic acid N′-(2-fluoro-phenyl)-hydrazide) as abrown-red solid. MS (APCI): (M+1)=264. ¹H and ¹⁹F NMR spectra agreedwith the structure. The solid was used in the next step without anyfurther purification.

A 500-ml, 3-necked, round bottomed-flask equipped with a magneticstirrer, an addition funnel and a thermometer was charged with asuspension of Intermediate 22 (10.00 g, 38 mmol) in 1 N HCl (130 ml) andethanol (130 ml). The suspension was heated to 76° C., which caused thesolid to fully dissolve. A solution of NaNO₂ (5.24 g, 76 mmol) in water(12 ml) was added dropwise over 15 minutes. Gas evolution was observedand, after a few minutes, a beige solid crashed out of solution. Whenthe NaNO₂ solution addition was complete, the mixture was refluxed for 1hour. The mixture was allowed to cool to room temperature and the solidwas filtered, washed with water (3×50 ml) and dried at 50° C. for 24hours in a vacuum oven at 17 torr to give 4.18 g (92%) of Intermediate23 (5-fluoro-1-(2-fluoro-phenyl)-1H-indazol-3-ol) as a beige solid. MS(APCI): (M+1)=247. ¹H and ¹⁹F NMR spectra agreed with the structure. Thesolid was used in the next step without any further purification.

Intermediate 23 (9.86 g, 40 mmol) was dissolved in DMF (100 ml). K₂CO₃(8.30 g, 60 mmol) was added and the mixture was stirred at roomtemperature for 10 minutes. Then a solution of(S)-3-methanesulfonyloxy-methyl-piperidine-1-carboxylic acid tert-butylester Intermediate 11 (11.75 g, 40 mmol) in 10 ml of DMF was added inone portion and the resulting mixture was stirred at 80-85° C. for 18hours. Saturated, aqueous NH₄Cl solution (200 ml) and water (1 L) wereadded and the aqueous phase was extracted with MTBE (methyl tert-butylether) (3×200 ml). The combined organic extracts were washed twice with100 ml of water, then saturated brine, and dried over MgSO₄. The solventwas removed under vacuum to give a brown solid that was passed through aplug of silica gel (hexanes/ethyl acetate 3/1 as mobile phase) to give16.37 g (92% yield) of Intermediate 24((S)-3-[5-fluoro-1-(2-fluoro-phenyl)-1H-indazol-3-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester) as a very thick yellow oil. MS (APCI): (M+1)=444.¹H and ¹⁹F NMR spectra agreed with the structure.

Intermediate 24 (20.6 g, 46 mmol) was dissolved in ethyl acetate (150ml) and the solution was cooled in an ice water bath. 4 M HCl in dioxane(150 ml) was added in one portion and the mixture was allowed to warm upto room temperature. After 1 hour the solvent was removed under vacuumto give a very thick, pale yellow oil. Ethyl acetate was added toredissolve the oil and removed under vacuum to give a foamy, yellowsolid. Diethyl ether (300 ml) was added to the oil and the suspensionwas slurried for 18 hours at room temperature. The resulting solid wasfiltered, washed twice with 50 ml of diethyl ether and dried in a vacuumoven at 50° C. for 24 hours to give 15.39 g (87%) of(S)-5-fluoro-1-(2-fluoro-phenyl)-3-(piperidin-3-ylmethoxy)-1H-indazolehydrochloride as a pale yellow solid. MS (APCI): (M+1)=344. ¹H and ¹⁹FNMR spectra agreed with the structure.

(S)-5-Fluoro-1-(2-fluoro-phenyl)-3-(piperidin-3-ylmethoxy)-1H-indazolehydrochloride (14.0 g, 37 mmol) was suspended in ethyl acetate (100 ml)and a 1 M solution of K₂CO₃ in water (100 ml) was added. The resultingmixture was vigorously stirred, which caused the solid to dissolvecompletely. After 1 hour, the two layers were separated and the aqueouslayer was extracted twice with 50 ml of ethyl acetate. The combinedorganic extracts were washed with brine and dried over MgSO₄. Thesolvent was removed under vacuum to give 11.9 g (94%) of the free base(S)-5-fluoro-1-(2-fluoro-phenyl)-3-(piperidin-3-ylmethoxy)-1H-indazoleas a very thick yellow oil. ¹H and ¹⁹F NMR spectra agreed with thestructure.

The free base (20.9 g, 61 mmol) was dissolved in methanol (200 ml).L-tartaric acid (9.1 g, 61 mmol) was added in one portion and themixture was stirred at room temperature for 10 minutes to give a clearsolution. The solvent was removed under vacuum to give a pale yellowsolid, which was slurried in diethyl ether (500 ml) for 2 hours. Thesolid was filtered, washed with diethyl ether (50 ml) and dried invacuum oven at 50° C. and 17 torr for 2 hours and then at roomtemperature for 48 hours to give 27.8 g (93%) of the L-tartrate salt(S)-5-fluoro-1-(2-fluorophenyl)-3-(piperidin-3-ylmethoxy)-1H-indazoleL-tartrate as a white solid. ¹H and ¹⁹F NMR spectra agreed with thestructure. HPLC: chemical purity: 98.7% a/a; chiral: 100% ee. Combustion(CHN) analysis: passed.

Examples 108-111 were synthesized in a manner similar to that describedfor Example 107, except Cs₂CO₃ was used instead of K₂CO₃ and HCl wasused for deprotection and salt formation.

Ex. # NAME MS MP (° C.) CHN NMR and [α]_(D) ²⁴ 1 1-(2-Fluorophenyl)-210-211° C. 3-(piperidin-4-yloxy)- Found for C₁₈H₁₈FN₃O•HCl•0.25H₂O: C,61.32; H, 5.59; N, 1H-indazole 11.71; F, 5.39; Cl, 10.09 hydrochloride¹H NMR(400MHz, DMSO-D₆) δppm 2.06(m, 2H), 2.28(ddd, J=10.31, 7.02,3.42Hz, 2H), 3.11(ddd, J=12.63, 8.60, 3.66Hz, 2H), 3.26(m, 2H),5.11(ddd, J=11.35, 7.56, 3.54Hz, 1H), 7.19(t, J=7.44Hz, 1H), 7.27(dd,J=8.54, 3.42Hz, 1H), 7.37(dt, J=8.48, 4.18Hz, 1H), 7.46(dd, J=8.30,0.98Hz, 1H), 7.49(m, 2H), 7.62(m, 1H), 7.75(d, J=8.05Hz, 1H), 9.09(s,2H) 2 (S)-(+)-1-(2- MS(APCI)M+1=328 Fluorophenyl)-3- 158-160° C.(morpholin-2- Found for C₁₈H₁₈FN₃O2•C₄H₄O₄: C, 59.71; H, 4.84; N, 9.44;F, ylmethoxy)-1H- 4.44 indazole maleate ¹H NMR(400MHz, DMSO-D6) δppm3.03(td, J=12.20, 3.42Hz, 2H), 3.21(d, J=13.18Hz, 1H), 3.39(d,J=11.96Hz, 1H), 3.74(td, J=12.38, 2.56Hz, 1H), 4.03(dd, J=12.57, 3.05Hz,1H), 4.15(m, 1H), 4.45(ddd, J=14.76, 11.47, 4.76Hz, 2H), 5.99(m, 2H),7.21(m, 1H), 7.28(dd, J=8.54, 3.66Hz, 1H), 7.38(m, 1H), 7.49(m, 3H),7.61(m, 1H), 7.73(d, J=8.05Hz, 1H), 8.82(s, 2H) [α]_(D) ²⁴=+2.9degrees(MeOH, c=6.5) 3 (S)-(+)-1-(2,4- MS(APCI)M+1=346Difluorophenyl)-3- 150-151° C. (morpholin-2- Found forC₁₈H₁₇F₂N₃O2•C₄H₄O₄: C 57.09; H, 4.42; N, 8.99; F, ylmethoxy)-1H- 8.02indazole maleate [α]_(D) ²⁴=+1.6 degrees(MeOH, c=5.1) 41-(2-Fluorophenyl)- MS(APCI)M+1=326 3-(piperidin-3- 131-133° C.ylmethoxy)-1H- Found for C₁₉H₂OFN₃O•HCl.0.4H₂O: C, 61.87; H, 6.16; N,indazole 11.37; F, 5.08; Cl, 9.61 hydrochloride 5 (R)-(−)-1-(2-MS(APCI)M+1=328 Fluorophenyl)-3- 103-104° C. (morpholin-2- Found forC₁₈H₁₈FN₃O₂•HCl•0.15H₂O: C, 59.00; H, 5.32; N, ylmethoxy)-1H- 11.12; F,5.42; Cl, 9.55 indazole [α]_(D) ²⁴=−4 degrees(MeOH, c=5.0) hydrochloride6 (S)-(−)-1-(2- MS(APCI)M+1=326 Fluorophenyl)-3- 196-197° C.(piperidin-3- Found for C₁₉H₂0FN₃O•HCl•0.2H₂O: C, 62.45; H, 5.96; N,11.22; ylmethoxy)-1H- F, 5.19; Cl, 9.69 indazole [α]_(D) ²⁴=−15.7degrees(MeOH, c=5.1) hydrochloride 7 (S)-(−)-1-(2- MS(APCI)M+1=312Fluorophenyl)-3- 100-101° C. (pyrrolidin-3- Found forC₁₈H₁₈FN₃O•HCl•0.45H₂O: C, 60.78; H, 5.70; N, ylmethoxy)-1H- 11.97; F,5.43; Cl, 9.96 indazole [α]_(D) ²⁴=−1 degree(MeOH, c=5.0) hydrochloride8 (S)-1-(2,4-Difluoro- MS(APCI)M+1=330.1 phenyl)-3- Found forC₁₈H₁₇F₂N₃O HCl•0.47 H₂O; C, 57.38; H, 4.91; N, (pyrrolidin-3- 10.99; F,9.78; Cl, 9.68 ylmethoxy)-1H- ¹H NMR(400MHz, DMSO-D6) δppm 1.8(m, 1H),2.1(m, 1H), indazole 2.9(m, 1H), 3.1(dd, J=11.7, 7.1Hz, 1H), 3.2(m, 1H),3.3(m, 1H), hydrochloride 3.4(dd, J=11.8, 8.2Hz, 1H), 4.4(m, 2H), 7.2(t,J=7.4Hz, 1H), 7.3(m, 2H), 7.5(m, 1H), 7.6(m, 1H), 7.7(td, J=8.9, 5.9Hz,1H), 7.8(d, J=8.1Hz, 1H), 9.1(bs, 2H). 9 (R)-1-(2,4-Difluoro-MS(APCI)M+1=330.1 phenyl)-3- Found for C₁₈H₁₇F₂N₃O HCl•0.38 H₂O; C,57.64; H, 4.94; N, (pyrrolidin-3- 11.16; F, 9.80; Cl, 9.61ylmethoxy)-1H- ¹H NMR(400MHz, DMSO-D6) δppm 1.8(m, 1H), 2.1(m, 1H),indazole 2.9(m, 1H), 3.1(dd, J=11.7, 7.1Hz, 1H), 3.2(m, 1H), 3.3(m, 1H),hydrochloride 3.4(dd, J=11.6, 7.9Hz, 1H), 4.4(m, 2H), 7.2(m, 1H), 7.3(m,2H), 7.5(m, 1H), 7.6(m, 1H), 7.7(td, J=8.9, 6.1Hz, 1H), 7.8(d, J=8.1Hz,1H), 9.1(bs, 2H) 10 1-(2,4-Difluoro- MS(APCI)M+1=330.1phenyl)-3-(piperidin- Found for C₁₈H₁₇F₂N₃O•1.2 HCl; C, 58.32; H, 4.88;N, 11.22; F, 4-yloxy)-1H-indazole 9.61; Cl, 11.37 hydrochloride ¹HNMR(400MHz, DMSO-D6) δppm 2.1(m, 2H), 2.3(m, 2H), 3.1(m, 2H), 3.3(m,2H), 5.1(m, 1H), 7.2(m, 1H), 7.3(m, 2H), 7.5(m, 1H), 7.6(m, 1H), 7.7(td,J=8.9, 6.1Hz, 1H), 7.8(d, J=9.0Hz, 1H), 9.0(bs, 2H). 11 (R)-1-(2-Fluoro-MS(APCI)M+1=312.1 phenyl)-3- Found for C₁₈H₁₈F₁N₃O1.05 HCl•0.46 H₂O; C,60.33; H, 5.59; (pyrrolidin-3- N, 11.61; F, 5.40; Cl, 10.77ylmethoxy)-1H- ¹H NMR(400MHz, DMSO-D6) δppm 1.8(m, 1H), 2.1(m, 1H),indazole 2.9(m, 1H), 3.1(m, 1H), 3.2(m, 1H), 3.3(m, 1H), 3.4(dd,hydrochloride J=11.5, 8.1Hz, 1H), 4.4(m, 2H), 7.2(t, J=7.6Hz, 1H),7.3(dd, J=8.5, 3.7Hz, 1H), 7.4(m, 1H), 7.5(m, 3H), 7.6(t, J=7.8Hz, 1H),7.8(d, J=7.8Hz, 1H), 9.2(bs, 2H). 12 (S)-(−)-1-(2- MS(APCI)M+1=298Fluorophenyl)-3- 130-131° C. (pyrrolidin-2-yloxy)- Found forC₁₇H₁₆FN₃O•1.05HCl•0.3H₂O: C, 59.98; H, 5.27; N, 1H-indazole 12.26; F,5.53; Cl, 10.76 hydrochloride [α]_(D) ²⁴=−10.5 degrees(MeOH, c=6.1) 13(R)-(+)-1-(2- MS(APCI)M+1=298 Fluorophenyl)-3- 116-117° C.(pyrrolidin-2-yloxy)- Found for C₁₇H₁₆FN₃O•C4H4O4: C, 60.97; H, 4.81; N,10.13; F, 1H-indazole maleate 4.67 [α]_(D) ²⁴=+10.1 degrees(MeOH, c=7.3)14 (R)-1-Phenyl-3- MS(APCI)M+1=294.1 (pyrrolidin-3- Found forC₁₈H₁₉N₃O.1.0 HCl•0.23 H₂O; C, 64.35; H, 6.17; N, ylmethoxy)-1H- 12.21;Cl, 10.52 indazole ¹H NMR(400MHz, DMSO-D6) δppm 1.9(m, 1H), 2.2(m, 1H),hydrochloride 2.9(m, 1H), 3.1(m, 1H), 3.2(m, 1H), 3.3(m, 1H), 3.4(dd,J=11.7, 8.1Hz, 1H), 4.5(m, 2H), 7.2(m, 1H), 7.3(t, J=7.9Hz, 1H), 7.5(m,3H), 7.7(d, J=8.8Hz, 2H), 7.8(dd, J=15.7, 8.9Hz, 2H), 9.2(bs, 2H). 15(±)-1-Phenyl-3- MS(APCI)M+1=294 (piperidin-3-yloxy)- 183-184° C.1H-indazole Found for C₁₈H₁₉N₃O•HCl: C, 65.31; H, 6.15; N, 12.66; Cl,10.72 hydrochloride 16 (±)-1-Phenyl-3- MS(APCI)M+1=308 (piperidin-3-215-216° C. ylmethoxy)-1H- Found for C₁₉H₂₁N₃O•HCl: C, 66.41; H, 6.43;N, 12.05; Cl, 10.40 indazole hydrochloride 17 (±)-1-Phenyl-3-MS(APCI)M+1=308 (piperidin-4- 218-219° C. ylmethoxy)-1H- Found forC₁₉H₂₁N₃O•HCl: C, 66.22; H, 6.56; N, 12.01; Cl, 10.32 indazolehydrochloride 18 (R)-(+)-1-Phenyl-3- MS(APCI)M+1=308 (piperidin-3-163-164° C. ylmethoxy)-1H- Found for C₁₉H₂₁N₃O•HCl: C, 66.04; H, 6.50;N, 12.13; Cl, 10.35 indazole [α]_(D) ²⁴=+14.4 degrees(MeOH, c=5.0)hydrochloride 19 (S)-(−)-1-Phenyl-3- MS(APCI)M+1=308 (piperidin-3-165-166° C. ylmethoxy)-1H- Found for C₁₉H₂₁N₃O•HCl: C, 66.02; H, 6.49;N, 12.04; Cl, 10.11 indazole [α]_(D) ²⁴=−17.1 degrees(MeOH, c=4.9)hydrochloride 20 1-Phenyl-3- MS(APCI)M+1=294 (piperidin-4-yloxy)-154-156° C. 1H-indazole Found for C₁₈H₁₉N₃O•HCl: C, 65.28; H, 6.05; N,12.58; Cl, 10.90 hydrochloride 21 (S)-(+)-3-(Morpholin- MS(APCI)M+1=3102-ylmethoxy)-1- 165-166° C. phenyl-1H-indazole Found for C₁₈H₁₉N₃O₂•HCl:C, 62.22; H, 5.79; N, 12.00; Cl, hydrochloride 10.54 [α]_(D) ²⁴=+3.3degrees(MeOH, c=10.2) 22 (S)-1-Phenyl-3- MS(APCI)M+1=294.1(pyrrolidin-3- Found for C₁₈H₁₉N₃O•1.05 HCl•0.39 H₂O; C, 63.79; H, 5.96;N, ylmethoxy)-1H- 12.12; Cl, 11.16 indazole ¹H NMR(400MHz, DMSO-D6) δppm1.9(m, 1H), 2.2(m, 1H), hydrochloride 2.9(m, 1H), 3.1(m, 1H), 3.2(m, 1H)3.3(m, 1H), 3.4(dd, J=11.6, 7.9Hz, 1H), 4.5(m, 2H), 7.2(m, 1H), 7.3(t,J=7.4Hz, 1H), 7.5(m, 3H), 7.7(d, J=7.6Hz, 2H), 7.8(dd, J=14.9, 8.3Hz,2H), 9.3(bs, 2H). 23 (S)-1-(3,4-Difluoro- 177-179° C. phenyl)-3- Foundfor C₁₈H₁₇F₂N₃O₂•1.05 HCl•0.15 H₂O; C, 55.67; H, (morpholin-2- 4.43; N,10.67; Cl, 9.38; F, 10.00 ylmethoxy)-1H- indazole hydrochloride 24(S)-1-(2,6-Difluoro- 217-218° C. phenyl)-3- Found for C₁₉H₁₉F₂N₃O1•1.0HCl; C, 56.45; H, 4.55; N, 10.95; (morpholin-2- Cl, 9.26 ylmethoxy)-1H-[α]_(D) ²⁴=+2.2 degrees(MeOH, c=7.2) indazole hydrochloride 25(S)-1-(2,6-Difluoro- 139-141° C. phenyl)-3-(piperidin- Found forC₁₉H₁₉F₂N₃O1•1.0 C₄H₄O₄; C, 59.76; H, 5.02; N, 3-ylmethoxy)-1H- 8.99; F,8.27 indazole maleate [α]_(D) ²⁴=−8.9 degrees(MeOH, c=7.2) 26(S)-1-(2,5-Difluoro- 169-170° C. phenyl)-5-fluoro-3- Found forC₁₈H₁₆F₃N₃O₂•C₄H₄O₄: C, 55.10; H, 4.14; N, 8.67; (morpholin-2- F, 11.91ylmethoxy)-1H- [α]_(D) ²⁴=+4.2 degrees(MeOH, c=8.8) indazole maleate 271-(2,5-Difluoro- MS(APCI)M+1=330.1 phenyl)-3-(piperidin- Found forC₁₈H₁₇F₂N₃O•1.0 HCl; C, 58.78; H, 4.79; N, 11.35; F,4-yloxy)-1H-indazole 10.24; Cl, 9.92 hydrochloride ¹H NMR(400MHz,DMSO-D6) δppm 2.1(m, 2H), 2.3(m, 2H), 3.1(m, 2H), 3.3(m, 2H), 5.1(m,1H), 7.2(t, J=7.9Hz, 1H), 7.4(m, 2H), 7.5(m, 3H), 7.8(d, J=8.1Hz, 1H),8.8(bs, 2H). 28 (S)-(+)-1-(2,5- MS(APCI)M+1=346 Difluorophenyl)-3-156-157° C. (morpholin-2- Found for C₁₈H₁₇F₂N₃O₂•C₄H₄O₄: C, 57.44; H,4.64; N, 9.08; ylmethoxy)-1H- F, 8.26 indazole maleate [α]_(D) ²⁴=+3.8degrees(MeOH, c=5.5) 29 1-(3,5-Dichloro- MS(APCI)M+1=362.1phenyl)-3-(piperidin- ¹H NMR(400MHz, DMSO-D6) δppm 2.1(m, 2H), 2.3(m,2H), 4-yloxy)-1H-indazole 3.2(ddd, J=12.6, 8.6, 3.7Hz, 2H), 3.3(m, 2H),5.2(ddd, J=7.6, hydrochloride 4.1, 3.9Hz, 1H), 7.3(m, 1H), 7.5(t,J=1.8Hz, 1H), 7.6(ddd, J=8.5, 7.1, 1.0Hz, 1H), 7.8(m, 3H), 7.9(d,J=8.5Hz, 1H), 8.8(s, 2H) 30 (R)-1-(2,5-Difluoro- MS(APCI)M+1=330.1phenyl)-3- ¹H NMR(400MHz, DMSO-D6) δppm 1.8(m, 1H), 2.1(m, 1H),(pyrrolidin-3- 2.9(m, 1H), 3.1(dd, J=11.7, 7.1Hz, 1H), 3.2(m, 1H),3.3(m, 1H), ylmethoxy)-1H- 3.4(dd, J=11.6, 7.9Hz, 1H), 4.4(m, 2H),7.2(t, J=7.2Hz, 1H), indazole 7.4(m, 2H), 7.6(m, 3H), 7.8(d, J=8.1Hz,1H), 9.1(bs, 2H). hydrochloride 31 (±)-1-(2,5-Difluoro-MS(APCI)M+1=344.2 phenyl)-3-(piperidin- Found for C₁₉H₁₉F₂N₃O•1.0HCl•0.03 H₂O; C, 59.72; H, 5.36; N, 3-ylmethoxy)-1H- 10.78; F, 9.59; Cl,9.38 indazole ¹H NMR(400MHz, DMSO-D6) δppm 1.4(m, 1H), 1.7(m, 1H),hydrochloride 1.9(m, 2H), 2.4(m, 1H), 2.8(m, 2H), 3.2(d, J=11.5Hz, 1H),3.4(d, J=11.5Hz, 1H), 4.3(dd, J=10.4, 7.2Hz, 1H), 4.4(m, 1H), 7.2(t,J=7.4Hz, 1H), 7.4(m, 2H), 7.6(m, 3H), 7.8(d, J=8.1Hz, 1H), 9.0(m, 1H),9.1(m, 1H). 32 (S)-1-(2,5-Difluoro- MS(APCI)M+1=330.1 phenyl)-3- Foundfor C₁₈H₁₇F₂N₃O•1.0 HCl•0.40 H₂O; C, 58.30; H, 4.96; N, (pyrrolidin-3-11.12; F, 9.79; Cl, 9.81 ylmethoxy)-1H- ¹H NMR(400MHz, DMSO-D6) δppm1.8(m, 1H), 2.1(m, 1H), indazole 2.9(m, 1H), 3.1(m, 1H), 3.2(m, 1H),3.3(m, 1H), 3.4(m, 1H), hydrochloride 4.4(m, 2H), 7.2(t, J=7.4Hz, 1H),7.4(m, 2H), 7.6(m, 3H), 7.8(d, J=8.1Hz, 1H), 9.3(bs, 2H). 33(S)-1-(3,4-Difluoro- MS(APCI)M+1=344.2 phenyl)-3-(piperidin- ¹HNMR(400MHz, DMSO-D6) δppm 1.36(m, 1H), 1.77(m, 3H), 3-ylmethoxy)-1H-2.38(m, 2H), 2.77(m, 2H), 3.20(d, J=12.45Hz, 1H), 3.36(d, indazoleJ=11.96Hz, 1H), 4.33(m, 2H), 7.20(t, J=7.45Hz, 1H), 7.53(m,hydrochloride 3H), 7.75(m, 3H), 9.06(s, 2H). 34 1-(3,4-Difluoro-MS(APCI)M+1=330.2 phenyl)-3-(piperidin- ¹H NMR(400MHz, DMSO-D6) δppm2.04(m, 2H), 2.27(m, 2H), 4-yloxy)-1H-indazole 3.10(m, 2H), 3.24(dd,J=7.32, 4.15Hz, 2H), 5.14(m, 1H), 7.20(t, hydrochloride J=7.20Hz, 1H),7.54(m, 3H), 7.76(m, 3H), 9.05(bs, 2H) 35 (S)-1-(3,4-Difluoro-MS(APCI)M+1=330.2 phenyl)-3- ¹H NMR(400MHz, DMSO-D6) δppm 1.79(m, 1H),2.11(m, 1H), (pyrrolidin-3- 2.85(m, 1H), 3.06(dd, J=11.47, 7.08Hz, 1H),3.14(m, 1H), ylmethoxy)-1H- 3.24(m, 1H), 3.35(dd, J=11.60, 7.93Hz, 1H),4.43(m, 2H), 7.20(t, indazole J=7.20Hz, 1H), 7.54(m, 3H), 7.76(m, 3H),9.15(bs, 2H). hydrochloride 36 1-(2,6-Difluoro- MS(APCI)M+1=330.2phenyl)-3-(piperidin- ¹H NMR(400MHz, DMSO-D6) δppm 2.00(m, 2H), 2.23(m,2H), 4-yloxy)-1H-indazole 3.07(m, 2H), 3.24(m, 2H), 5.04(m, 1H), 7.17(m,2H), 7.36(t, hydrochloride J=8.42Hz, 2H), 7.44(m, 1H), 7.60(m, 1H),7.73(d, J=8.06Hz, 1H), 9.01(bs, 2H). 37 (S)-1-(2,6-Difluoro-MS(APCI)M+1=330.2 phenyl)-3- ¹H NMR(400MHz, DMSO-D6) δppm 1.78(m, 1H),2.08(m, 1H), (pyrrolidin-3- 2.81(m, 1H), 3.19(m, 4H), 4.34(m, 2H),7.17(m, 2H), 7.36(t, ylmethoxy)-1H- J=8.30Hz, 2H), 7.44(m, 1H), 7.60(m,1H), 7.73(m, J=8.06Hz, indazole 1H), 9.32(bs, 2H). hydrochloride 38(S)-1-(2,5-Difluoro- MS(APCI)M+1=344.2 phenyl)-3-(piperidin- ¹HNMR(400MHz, DMSO-D6) δppm 1.4(m, 1H), 1.7(m, 1H), 3-ylmethoxy)-1H-1.9(m, 2H), 2.4(m, 1H), 2.8(m, 2H), 3.2(d, J=12.7Hz, 1H), indazole3.4(m, J=12.6, 2.6Hz, 1H), 4.3(m, 2H), 7.2(t, J=7.4Hz, 1H),hydrochloride 7.4(m, 2H), 7.6(m, 3H), 7.8(d, J=7.8Hz, 1H), 8.9(bs, 2H).39 1-(2,5-Difluoro- MS(APCI)M+1=348.2 phenyl)-5-fluoro-3- ¹H NMR(400MHz,DMSO-D6) δppm 2.1(m, 2H), 2.3(m, 2H), (piperidin-4-yloxy)- 3.1(m, 2H),3.3(m, 2H), 5.1(dq, J=7.4, 3.7Hz, 1H), 7.4(m, 3H), 1H-indazole 7.6(m,3H), 9.1(s, 1H). hydrochloride 40 (R)-1-(2,5-Difluoro- MS(APCI)M+1=348.2phenyl)-5-fluoro-3- ¹H NMR(400MHz, DMSO-D6) δppm 1.8(m, 1H), 2.1(td,(pyrrolidin-3- J=13.2, 7.8Hz, 1H), 2.9(dt, J=14.3, 7.1Hz, 1H), 3.1(dd,J=11.6, ylmethoxy)-1H- 7.0Hz, 1H), 3.2(m, 1H), 3.3(m, 2H), 4.4(ddd,J=17.1, 10.4, 6.7Hz, indazole 2H), 7.4(m, 3H), 7.5(m, 3H), 9.3(s, 1H).hydrochloride 41 1-(4-Chloro-phenyl)- MS(APCI)M+1=328.13-(piperidin-4-yloxy)- ¹H NMR(400MHz, DMSO-D6) δppm 2.1(m, 2H), 2.3(m,2H), 1H-indazole 3.1(ddd, J=12.6, 8.5, 3.8Hz, 2H), 3.3(m, 2H), 5.2(ddd,J=7.5, hydrochloride 4.0, 3.8Hz, 1H), 7.2(t, J=7.4Hz, 1H), 7.5(ddd,J=8.5, 7.1, 1.2Hz, 1H), 7.6(m, 2H), 7.8(m, 4H), 8.9(s, 2H) 421-(4-Fluoro-phenyl)- MS(APCI)M+1=312.2 3-(piperidin-4-yloxy)- ¹HNMR(400MHz, DMSO-D6) δppm 2.0(m, 2H), 2.3(m, 2H), 1H-indazole 3.1(ddd,J=12.7, 8.6, 3.5Hz, 2H), 3.3(m, 2H), 5.1(dt, J=7.6, 3.9Hz, hydrochloride1H), 7.2(t, J=7.2Hz, 1H), 7.4(m, 2H), 7.5(ddd, J=8.4, 7.1, 1.1Hz, 1H),7.7(m, 4H), 8.8(s, 2H) 43 1-(3-Fluoro-phenyl)- MS(APCI)M+1=312.23-(piperidin-4-yloxy)- ¹H NMR(400MHz, DMSO-D6) δppm 2.0(m, 2H), 2.3(m,2H), 1H-indazole 3.1(m, 2H), 3.3(m, 2H), 5.2(m, 1H), 7.1(m, 1H), 7.2(m,1H), hydrochloride 7.6(m, 4H), 7.8(d, J=7.8Hz, 1H), 7.9(d, J=8.5Hz, 1H),8.7(s, 2H) 44 (S)-(−)-3-(Piperidin- MS(APCI)M+1=309 3-ylmethoxy)-1-181-183° C. pyridin-2-yl-1H- Found for C₁₈H₂₀N₄O•C₄H₄O₄: C, 62.24; H,5.38; N, 13.12 indazole maleate [α]_(D) ²⁴=−12.1 degrees(MeOH, c=6.6) 45(S)-(−)-5-Fluoro-1-(2- MS(APCI)M+1=344 fluorophenyl)-3- 141-142° C.(piperidin-3- Found for C₁₉H₁₉F₂N₃O•C₄H₄O₄: C, 59.76; H, 5.04; N, 9.10;F, ylmethoxy)-1H- 8.10 indazole maleate ¹H NMR(400MHz, DMSO-D6) δppm1.39(m, 1H), 1.63(m, 1H), 1.84(m, 2H), 2.31(m, 1H), 2.81(m, 2H), 3.25(d,J=13.18Hz, 1H), 3.43(dd, J=12.20, 3.66Hz, 1H), 4.26(dd, J=10.49, 7.08Hz,1H), 4.35(m, 1H), 5.99(s, 2H), 7.35(m, 3H), 7.51(m, 3H), 7.61(m, 1H),8.45(s, 2H) [α]_(D) ²⁴=−11.0 degrees(MeOH, c=5.8) 46 (S)-(+)-5-Fluoro-1-MS(APCI)M+1=346 (2-fluorophenyl)-3- 155-156° C. (morpholin-2- Found forC₁₈H₁₇F₂N₃O₂•C₄H₄O₄: C, 57.35; H, 4.55; N, 9.04; ylmethoxy)-1H- F, 8.10indazole maleate ¹H NMR(400MHz, DMSO-D6) δppm 3.03(m, 2H), 3.21(d,J=12.69Hz, 1H), 3.38(d, J=11.47Hz, 1H), 3.73(td, J=12.44, 2.44Hz, 1H),4.02(dd, J=12.81, 3.05Hz, 1H), 4.14(ddd, J=11.35, 6.83, 4.76Hz, 1H),4.44(ddd, J=13.97, 11.41, 4.64Hz, 2H), 5.99(s, 2H), 7.37(m, 3H), 7.51(m,3H), 7.62(m, 1H), 8.82(s, 2H) [α]_(D) ²⁴=+3.8 degrees(MeOH, c=6.1) 47(S)-(−)-5-Fluoro-1-(2- MS(APCI)M+1=326 fluorophenyl)-3- 205-207° C.(piperidin-3- Found for C₁₉H₂₀FN₃O•HCl: C, 62.75; H, 5.62; N, 11.49; F,5.39; ylmethoxy)-1H- Cl, 9.96 indazole [α]_(D) ²⁴=−13.1 degrees(MeOH,c=7.0) hydrochloride 48 (S)-(+)-1-(2,4- MS(APCI)M+1=364Difluorophenyl)-5- 151-152° C. fluoro-3-(morpholin- Found forC₁₈H₁₆F₃N₃O₂•C₄H₄O₄: C, 54.88; H, 4.14; N, 8.72; 2-ylmethoxy)-1H- F,12.29 indazole maleate [α]_(D) ²⁴=+3.2 degrees(MeOH, c=7.4) 49(S)-(−)-1-(2,4- MS(APCI)M+1=362 Difluorophenyl)-5- 201-203° C.fluoro-3-(piperidin-3- Found for C₁₉H₁₈F₃N₃O•HCl: C, 57.20; H, 4.75; N,10.48; F, ylmethoxy)-1H- 14.37; Cl, 8.99 indazole [α]_(D) ²⁴=−11.8degrees(MeOH, c=5.6) hydrochloride 50 (S)-1-(2,6-Difluoro- 247-249° C.phenyl)-5-fluoro-3- Found for C₁₈H₁₆F₃N₃O₂•1.0 HCl: C, 54.06; H, 4.19;N, 10.44; (morpholin-2- F, 14.41; Cl, 8.84 ylmethoxy)-1H- [α]_(D)²⁴=+2.1 degrees(MeOH, c=7.1) indazole hydrochloride 515-Fluoro-1-(2-fluoro- MS(APCI)M+1=330.1 phenyl)-3-(piperidin- Found forC₁₈H₁₇F₂N₃O1•1.0 HCl•0.85 H₂O; C, 56.34; H, 5.30; 4-yloxy)-1H-indazoleN, 10.87; F, 9.99; Cl, 9.41 hydrochloride ¹H NMR(400MHz, DMSO-D6) δppm2.1(m, 2H), 2.3(m, 2H), 3.1(m, 2H), 3.3(m, 2H), 5.1(m, 1H), 7.4(m, 3H),7.5(m, 2H), 7.6(dd, J=8.4, 2.3Hz, 1H), 7.6(t, J=7.8Hz, 1H), 9.1(bd,J=21.0Hz, 2H). 52 5-Fluoro-1-(2-fluoro- MS(APCI)M+1=358phenyl)-3-(1-methyl- ¹H NMR(400MHz, METHANOL-D4) δppm 1.3(s, 3H), 1.6(m,1H), piperidin-3- 1.9(m, 3H), 3.2(m, 4H), 3.3(s, 1H), 4.3(m, 2H), 7.3(m,2H), ylmethoxy)-1H- 7.4(m, 2H), 7.4(m, 2H), 7.6(m, 1H). indazolehydrogen chloride 53 1-(2-Fluoro-phenyl)- MS(APCI)M+1=340 3-(3-methyl-¹H NMR(400MHz, METHANOL-D4) δppm 1.3(s, 3H), 1.7(m, 1H), piperidin-3-1.9(m, 3H), 3.2(m, 3H), 3.3(s, 1H), 4.4(m, 2H), 7.2(m, 2H),ylmethoxy)-1H- 7.4(m, 2H), 7.5(m, 2H), 7.6(m, 1H), 7.7(d, J=8.1Hz, 1H).indazole hydrogen chloride 54 5-Fluoro-1-(2-fluoro- MS(APCI)M+1=358phenyl)-3-(4-methyl- ¹H NMR(400MHz, METHANOL-D4) δppm 1.3(s, 3H) 1.8(m,2H), piperdin-4- 2.0(m, 2H) 3.2(m, 3H) 3.3(m, 2H) 4.3(s, 2H) 7.3(m, 2H)ylmethoxy)-1H- 7.4(m, 3H) 7.5(m, 1H) 7.6(m, 1H). indazole hydrogenchloride 55 (R)-5-Fluoro-1-(2- MS(APCI)M+1=344 fluoro-phenyl)-3- ¹HNMR(400MHz, METHANOL-D4) δppm 1.5(m, 1H), 1.8(m, (piperidin-3- 1H),2.0(d, J=12.2Hz, 2H), 2.4(m, 1H), 3.0(m, 2H), 3.4(d, ylmethoxy)-1H-J=12.9Hz, 1H), 3.6(d, J=15.9Hz, 1H), 4.3(m, 1H), 4.5(m, 1H), indazolemaleate 6.2(s, 2H), 7.3(m, 2H), 7.4(m, J=25.4Hz, 3H), 7.5(m, 1H), 7.6(m,1H). 56 1-(2,4-Difluoro- MS(APCI)M+1=348.1 phenyl)-5-fluoro-3- Found forC₁₈H₁₆F₃N₃O1•1.0 HCl•0.12 H₂O; C, 55.62; H, 4.31; (piperidin-4-yloxy)-N, 10.61; F, 14.57; Cl, 9.11 1H-indazole ¹H NMR(400MHz, DMSO-D₆) δppm2.1(m, 2H), 2.2(m, 2H), hydrochloride 3.1(m, 2H), 3.3(m, 2H), 5.1(m,1H), 7.3(m, 2H), 7.4(td, J=9.0, 2.4Hz, 1H), 7.6(m, 2H), 7.7(td, J=8.8,6.0Hz, 1H), 8.9(bs, 2H). 57 (±)-5-Fluoro-1-(2- MS(APCI)M+1=344.1fluoro-phenyl)-3- Found for C₁₉H₁₉F₂N₃O1•1.0 HCl•0.29 H₂O; C, 58.87; H,5.23; (piperidin-3- N, 10.87; F, 9.62; Cl, 9.49 ylmethoxy)-1H- ¹HNMR(400MHz, DMSO-D6) δppm 1.4(m, 1H), 1.8(m, 3H), indazole 2.4(m, 1H),2.8(m, 2H), 3.2(d, J=12.2Hz, 1H), 3.4(dd, J=12.3, hydrochloride 3.0Hz,1H), 4.3(dd, J=10.4, 7.0Hz, 1H), 4.4(m, 1H), 7.4(m, 3H), 7.5(m, 2H),7.6(dd, J=8.4, 2.1Hz, 1H), 7.6(m, 1H), 9.1(bs, 2H). 58 5-Chloro-1-(2,5-MS(APCI)M+1=364.1 difluoro-phenyl)-3- ¹H NMR(400MHz, DMSO-D₆) δppm2.1(m, 2H), 2.2(m, 2H), (piperidin-4-yloxy)- 2.3(d, J=3.9Hz, 1H),3.1(ddd, J=12.4, 8.1, 3.9Hz, 2H), 3.3(m, 1H-indazole 2H), 5.1(ddd,J=7.2, 3.8, 3.7Hz, 1H), 7.4(m, 2H), 7.5(m, 3H), hydrochloride 7.9(d,J=1.5Hz, 1H), 9.1(s, 2H) 59 7-Methyl-1-phenyl- MS(APCI)M+1=308.23-(piperidin-4-yloxy)- ¹H NMR(400MHz, DMSO-D6) δppm 2.0(m, 5H), 2.2(m,2H), 1H-indazole 3.1(td, J=8.7, 4.4Hz, 2H), 3.2(m, 2H), 5.0(ddd, J=7.7,4.0, 3.9Hz, hydrochloride 1H), 7.0(m, 1H), 7.2(d, J=7.1Hz, 1H), 7.5(m,5H), 7.5(d, J=7.8Hz, 1H), 8.7(s, 2H) 60 7-Methoxy-1-phenyl-MS(APCI)M+1=324.2 3-(piperidin-4-yloxy)- ¹H NMR(400MHz, DMSO-D6) δppm2.0(m, 2H), 2.2(ddd, 1H-indazole J=10.4, 7.1, 3.5Hz, 2H), 3.1(ddd,J=12.7, 8.7, 3.5Hz, 2H), hydrochloride 3.2(m, 2H), 3.7(s, 3H), 5.0(m,1H), 7.0(d, J=7.1Hz, 1H), 7.1(t, J=7.8Hz, 1H), 7.3(m, 2H), 7.4(m, 4H),8.9(s, 2H) 61 7-Chloro-1-phenyl- MS(APCI)M+1=328.13-(piperidin-4-yloxy)- ¹H NMR(400MHz, DMSO-D6) δppm 2.0(m, 2H), 2.2(m,2H), 1H-indazole 3.1(m, 2H), 3.3(m, 2H), 5.1(dt, J=7.6, 3.9Hz, 1H),7.2(m, 1H), hydrochloride 7.4(m, 5H), 7.5(m, 1H), 7.7(dd, J=8.1, 1.0Hz,1H), 8.8(s, 2H) 62 4-Methyl-1-phenyl- MS(APCI)M+1=308.23-(piperidin-4-yloxy)- ¹H NMR(400MHz, DMSO-D6) δppm 2.1(m, 2H), 2.3(m,2H), 1H-indazole 2.6(s, 3H), 3.2(m, 4H), 5.2(dt, J=6.6, 3.4Hz, 1H),6.9(d, J=7.1Hz, hydrochloride 1H), 7.3(m, 2H), 7.5(m, 3H), 7.7(dt,J=8.6, 1.7Hz, 2H), 9.0(s, 2H) 63 6-Fluoro-1-(2-fluoro- MS(APCI)M+1=330.1phenyl)-3-(piperidin- ¹H NMR(400MHz, DMSO-D6) δppm 2.0(m, 2H), 2.2(ddd,4-yloxy)-1H-indazole J=10.3, 7.1, 3.7Hz, 2H), 3.1(m, 2H), 3.2(m, 2H),5.1(ddd, hydrochloride J=7.7, 4.0, 3.9Hz, 1H), 7.1(m, 2H), 7.3(m, 1H),7.5(m, 2H), 7.6(m, 1H), 7.8(dd, J=8.8, 5.4Hz, 1H), 9.0(s, 2H) 646-Chloro-1-phenyl- MS(APCI)M+1=328.1 3-(piperidin-4-yloxy)- ¹HNMR(400MHz, DMSO-D6) δppm 2.0(m, J=14.2, 7.3, 3.7, 1H-indazole 3.5Hz,2H), 2.2(m, 2H), 3.1(m, 2H), 3.3(m, 2H), 5.1(dt, hydrochloride J=7.3,3.6Hz, 1H), 7.3(m, 1H), 7.5(m, 3H), 7.7(dt, J=8.7, 1.6Hz, 2H), 7.8(d,J=9.8Hz, 1H), 7.8(d, J=1.5Hz, 1H), 8.9(s, 2H) 65 1-(2-fluorophenyl)-3-MS(APCI)M+1=380.1 (piperidin-4-yloxy)-7- ¹H NMR(400MHz, DMSO-D6) δppm2.0(m, 2H), 2.2(m, 2H), (trifluoromethyl)-1H- 3.1(m, 2H), 3.2(m, 2H),5.0(ddd, J=7.8, 4.2, 4.0Hz, 1H), indazole 7.3(m, 3H), 7.6(m, J=7.7, 7.7,5.7, 1.8Hz, 2H), 7.8(d, J=7.3Hz, 1H), hydrochloride 8.1(d, J=7.8Hz, 1H),8.9(s, 2H) 66 (±)-1-(3-Fluoro- MS(APCI)M+1=326.2 phenyl)-3-(piperidin-¹H NMR(400MHz, DMSO-D6) δppm 1.4(m, 1H), 1.7(m, 1H), 3-ylmethoxy)-1H-1.9(m, 2H), 2.4(m, 1H), 2.8(m, 2H), 3.2(m, 1H), 3.4(dd, indazole J=12.2,3.4Hz, 1H), 4.3(dd, J=10.5, 7.1Hz, 1H), 4.4(m, 1H), hydrochloride 7.1(m,1H), 7.2(m, 1H), 7.6(m, 4H), 7.8(d, J=7.8Hz, 1H), 7.9(d, J=8.8Hz, 1H),8.7(s, 1H) 67 (±)-1-(4-Fluoro- MS(APCI)M+1=326.2 phenyl)-3-(piperidin-¹H NMR(400MHz, DMSO-D6) δppm 1.4(m, 1H), 1.7(m, 1H), 3-ylmethoxy)-1H-1.8(m, 2H), 2.4(m, 1H), 2.8(m, 2H), 3.2(m, 1H), 3.4(dd, indazole J=12.2,4.1Hz, 1H), 4.3(dd, J=10.5, 7.1Hz, 1H), 4.4(m, 1H), hydrochloride 7.2(m,1H), 7.4(m, 2H), 7.5(ddd, J=8.5, 7.1, 1.2Hz, 1H), 7.7(m, 4H), 8.7(s, 2H)68 (±)-1-(4-Chloro- MS(APCI)M+1=342.2 phenyl)-3-(piperidin- ¹HNMR(400MHz, DMSO-D6) δppm 1.4(qd, J=12.3, 3.8Hz, 1H), 3-ylmethoxy)-1H-1.7(m, 1H), 1.8(m, 2H), 2.4(m, 1H), 2.8(m, 2H), 3.2(d, indazoleJ=12.2Hz, 1H), 3.4(dd, J=12.5, 3.4Hz, 1H), 4.3(dd, J=10.5, 7.1Hz,hydrochloride 1H), 4.4(m, 1H), 7.2(m, 1H), 7.5(m, 3H), 7.7(m, 3H),7.8(d, J=8.5Hz, 1H), 8.8(s, 2H) 69 (±)-5-Chloro-1- MS(APCI)M+1=342.2phenyl-3-(piperidin- ¹H NMR(400MHz, DMSO-D6) δppm 1.4(m, 1H), 1.6(m,1H), 3-ylmethoxy)-1H- 1.8(m, 2H), 2.3(m, 1H), 2.8(m, 2H), 3.2(m, 1H),3.4(dd, indazol J=12.2, 3.7Hz, 1H), 4.3(dd, J=10.5, 7.1Hz, 1H), 4.4(m,1H), hydrochloride 7.3(m, 1H), 7.5(m, 3H), 7.7(ddd, J=8.7, 1.7, 1.6Hz,2H), 7.8(m, 2H), 8.7(s, 2H) 70 (±)-6-Fluoro-1-(2- MS(APCI)M+1=344.1fluoro-phenyl)-3- ¹H NMR(400MHz, DMSO-D6) δppm 1.4(td, J=12.2, 8.5Hz,1H), (piperidin-3- 1.7-1.8(m, 3H), 2.4(d, J=9.8Hz, 1H), 2.8(m, 2H),3.2(d, ylmethoxy)-1H- J=12.0Hz, 1H), 3.3(s, 1H), 3.4(m, 1H), 4.3(dd,J=10.5, 7.1Hz, indazole 1H), 4.3(m, 1H), 7.1(m, 2H), 7.4(m, 1H), 7.5(m,2H), 7.6(t, hydrochloride J=7.9Hz, 1H), 7.8(dd, J=8.8, 5.1Hz, 1H),9.0(s, 2H) 71 6-Methyl-1-phenyl- MS(APCI)M+1=308.23-(piperidin-4-yloxy)- ¹H NMR(400MHz, DMSO-D6) δppm 2.0(m, 2H), 2.3(m,2H), 1H-indazole 2.4(s, 3H), 3.1(ddd, J=12.7, 8.7, 3.8Hz, 2H), 3.3(m,2H), hydrochloride 5.1(ddd, J=7.4, 3.9, 3.8Hz, 1H), 7.0(d, J=8.3Hz, 1H),7.3(m, 1H), 7.5(m, 2H), 7.6(s, 1H), 7.6(d, J=8.3Hz, 1H), 7.7(dt, J=8.6,1.7Hz, 2H), 8.8(s, 2H) 72 1-(2-Fluoro-phenyl)- MS(APCI)M+1=326.26-methyl-3- ¹H NMR(400MHz, DMSO-D6) δppm 2.0(m, 2H), 2.3(ddd,(piperidin-4-yloxy)- J=10.4, 7.1, 3.3Hz, 2H), 2.4(s, 3H), 3.1(ddd,J=12.6, 8.7, 3.7Hz, 1H-indazole 2H), 3.3(dd, J=7.7, 4.5Hz, 2H), 5.1(ddd,J=7.7, 4.0, 3.9Hz, hydrochloride 1H), 7.0(m, 2H), 7.4(ddd, J=8.4, 5.4,3.1Hz, 1H), 7.5(m, 2H), 7.6(m, 2H), 8.8(s, 2H) 73 5-Chloro-1-(2-fluoro-Found for C₁₉H₁₉ClFN₃O•0.6HCl: C, 54.94; H, 4.54; N, 9.92.phenyl)-3-(piperidin- ¹H NMR(400MHz, DMSO-D6) δppm 1.4(m, 1H), 1.7(m,1H), 3-ylmethoxy)-1H- 1.8(m, 2H), 2.3(m, 1H), 2.8(m, 2H), 3.2(m, 1H),3.4(m, 1H), indazole 4.3(m, 1H), 4.4(m, 1H), 7.4(m, 2H), 7.5(m, 3H),7.8(s, 1H), hydrochloride 8.9(s, 2H). 74 1-(2-Fluoro-phenyl)-MS(APCI)M+1=340.2 6-methyl-3- ¹H NMR(400MHz, DMSO-D6) δppm 1.4(m, 1H),1.7(m, 1H), (piperidin-3- 1.8(m, 2H), 2.3(m, 1H), 2.4(s, 3H), 2.8(m,2H), 3.2(m, 1H), ylmethoxy)-1H- 3.4(m, 1H), 4.2(dd, J=10.5, 7.1Hz, 1H),4.3(m, 1H), 7.0(dd, indazole J=8.3, 0.7Hz, 1H), 7.0(d, J=3.4Hz, 1H),7.4(m, 1H), 7.5(m, 2H), hydrochloride 7.6(t, J=7.9Hz, 2H), 8.8(s, 2). 755,6-Difluoro-1-(2- MS(APCI)M+1=348.1 fluoro-phenyl)-3- ¹H NMR(400MHz,DMSO-D6) δppm 2.0(m, 2H), 2.2(m, 2H), (piperidin-4-yloxy)- 3.1(m, 2H),5.1(m, 1H), 7.4(m, 1H), 7.5(m, 3H), 7.6(m, 1H), 1H-indazole 7.9(m, 1H),8.8(m, 2H). hydrochloride 76 5,6-Difluoro-1-(2- MS(APCI)M+1=362.1fluoro-phenyl)-3- ¹H NMR(400MHz, DMSO-D6) δppm 1.4(m, 1H), 1.7(m, 1H),(piperidin-3- 1.8(m, 2H), 2.8(s, 2H), 3.4(s, 1H), 4.3(m, 2H),7.36-7.52(m, ylmethoxy)-1H- 5H), 7.60-7.64(m, 1H), 7.81-7.64(m, 1H),8.7(s, 2H). indazole hydrochloride 77 5-Fluoro-1-(3-fluoro-MS(APCI)M+1=330.1 phenyl)-3-(piperidin- ¹H NMR(400MHz, DMSO-D6) δppm2.1(m, 2H), 2.3(m, 2H), 4-yloxy)-1H-indazole 3.1(m, 2H), 3.3(m, 2H),5.2(dt, J=7.4, 3.8Hz, 1H), 7.1(m, 1H), hydrochloride 7.4(td, J=9.2,2.7Hz, 1H), 7.6(m, 4H), 7.9(dd, J=9.3, 3.9Hz, 1H), 8.8(s, 2H). 78(S)-5-Fluoro-1-(3- MS(APCI)M+1=344.1 fluoro-phenyl)-3- ¹H NMR(400MHz,DMSO-D6) δppm 1.4(m, 1H), 1.7(m, 1H), (piperidin-3- 1.8(m, 2H), 2.4(m,1H), 2.8(m, 2H), 3.2(m, 1H), 3.4(dd, ylmethoxy)-1H- J=12.4, 3.2Hz, 1H),4.3(dd, J=10.5, 7.1Hz, 1H), 4.4(m, 1H), indazole 7.1(m, 1H), 7.4(td,J=9.2, 2.4Hz, 1H), 7.6(m, 4H), 7.9(dd, hydrochloride J=9.3, 3.9Hz, 1H),8.9(s, 2H). 79 5-Fluoro-1-(4-fluoro- MS(APCI)M+1=330.1phenyl)-3-(piperidin- ¹H NMR(400MHz, DMSO-D6) δppm 2.0(m, 2H), 2.2(m,2H), 4-yloxy)-1H-indazole 3.1(m, 2H), 3.3(m, 2H), 5.1(ddd, J=7.4, 3.9,3.8Hz, 1H), hydrochloride 7.4(m, 3H), 7.6(dd, J=8.4, 2.1Hz, 1H), 7.7(m,3H), 8.7(s, 2H). 80 (S)-5-Fluoro-1-(4- MS(APCI)M+1=344.1fluoro-phenyl)-3- ¹H NMR(400MHz, DMSO-D6) δppm 1.4(m, 1H), 1.7(m, 1H),(piperidin-3- 1.8(m, 2H), 2.3(m, 1H), 2.8(q, J=11.5Hz, 2H), 3.2(d,J=12.5Hz, ylmethoxy)-1H- 1H), 3.4(m, 1H), 4.3(dd, J=10.5, 7.1Hz, 1H),4.4(m, 1H), indazole 7.4(m, 3H), 7.5(dd, J=8.3, 2.4Hz, 1H), 7.7(m, 3H),8.8(s, 2H). hydrochloride 81 4-Fluoro-1-(3-fluoro- MS(APCI)M+1=330.1phenyl)-3-(piperidin- ¹H NMR(400MHz, DMSO-D6) δppm 2.0(m, 2H), 2.3(m,2H), 4-yloxy)-1H-indazole 3.1(m, 2H), 3.2(m, 2H), 5.2(ddd, J=7.7, 4.0,3.9Hz, 1H), hydrochloride 7.0(dd, J=10.4, 7.7Hz, 1H), 7.2(m, 1H), 7.5(m,2H), 7.6(dt, J=6.9, 1.7Hz, 2H), 7.6(d, J=8.5Hz, 1H), 8.9(s, 2H). 82(S)-4-Fluoro-1-(3- MS(APCI)M+1=344.1 fluoro-phenyl)-3- ¹H NMR(400MHz,DMSO-D6) δppm 1.4(m, 1H), 1.7(m, 1H), (piperidin-3- 1.8(m, 2H), 2.4(m,1H), 2.8(m, 2H), 3.2(d, J=12.5Hz, 1H), ylmethoxy)-1H- 3.4(m, 1H), 4.3(m,2H), 7.0(dd, J=10.3, 7.8Hz, 1H), 7.2(m, 1H), indazole 7.5(m, 4H), 7.6(d,J=8.5Hz, 1H), 9.0(s, 2H). hydrochloride 83 4-Fluoro-1-(4-fluoro-MS(APCI)M+1=330.2 phenyl)-3-(piperidin- ¹H NMR(400MHz, DMSO-D6) δppm2.0(m, 2H), 2.2(m, 2H), 4-yloxy)-1H-indazole 3.1(m, 2H), 3.2(m, 2H),5.1(m, 1H), 6.9(m, 1H), 7.4(m, 2H), hydrochloride 7.4(m, 2H), 7.7(m,2H), 8.8(s, 2H). 84 (S)-4-Fluoro-1-(4- MS(APCI)M+1=344.2fluoro-phenyl)-3- ¹H NMR(400MHz, DMSO-D6) δppm 1.3(m, 1H), 1.6(m, 1H),(piperidin-3- 1.8(m, 2H), 2.3(m, 1H), 2.8(m, 2H), 3.2(m, 1H), 3.3(m,1H), ylmethoxy)-1H- 4.3(dd, J=10.5, 7.3Hz, 1H), 4.3(m, 1H), 6.9(m, 1H),7.4(m, 2H), indazole 7.4(m, 2H), 7.7(m, 2H), 8.7(s, 1H). hydrochloride85 (S)-4-Fluoro-1-(2- MS(APCI)M+1=344.2 fluoro-phenyl)-3- ¹H NMR(400MHz,DMSO-D6) δppm 1.3(m, 1H), 1.7(m, 1H), (piperidin-3- 1.8(m, 2H), 2.3(m,1H), 2.7(m, 2H), 3.2(d, J=12.5Hz, 1H), ylmethoxy)-1H- 3.3(m, 1H),4.2(dd, J=10.5, 7.3Hz, 1H), 4.3(m, 1H), 6.9(dd, indazole J=10.5, 7.8Hz,1H), 7.0(dd, J=8.4, 3.3Hz, 1H), 7.4(m, 2H), hydrochloride 7.5(m, 2H),7.6(td, J=7.9, 1.5Hz, 1H), 8.8(s, 1H). 86 5,6-Difluoro-1-MS(APCI)M+1=344.2 phenyl-3-(piperidin- ¹H NMR(400MHz, DMSO-D6) δppm1.4(m, 1H), 1.7(m, 1H), 3-ylmethoxy)-1H- 1.8(m, 2H), 2.4(m, 1H), 2.8(m,2H), 3.2(m, 1H), 3.4(m, 1H), indazole 4.3(m, 1H), 4.4(m, 1H), 7.3(m,1H), 7.5(m, 2H), 7.7(m, 2H), hydrochloride 7.9(m, 2H), 8.9(br s, 2H). 875,6-Difluoro-1- MS(APCI)M+1=330.2 phenyl-3-(piperidin- ¹H NMR(400MHz,DMSO-D6) δppm 2.1(m, 2H), 2.3(m, 2H), 4-yloxy)-1H-indazole 3.1(m, 2H),3.3(m, 2H), 5.1(m, 1H), 7.3(m, 1H), 7.5(m, 2H), hydrochloride 7.7(m,2H), 7.9(m, 2H), 9.0(br s, 2H). 88 1-(2,4-Difluoro- MS(APCI)M+1=348.2phenyl)-4-fluoro-3- ¹H NMR(400MHz, DMSO-D6) δppm 2.0(m, 2H), 2.2(m, 2H),(piperidin-4-yloxy)- 3.1(m, 2H), 3.2(m, 2H), 5.1(m, 1H), 7.0(dd, J=10.5,7.8Hz, 1H), 1H-indazole 7.1(dd, J=8.5, 2.7Hz, 1H), 7.3(m, 1H), 7.4(td,J=8.2, 5.1Hz, hydrochloride 1H), 7.6(ddd, J=11.2, 8.8, 2.9Hz, 1H),7.7(td, J=8.8, 6.0Hz, 1H), 8.7(s, 1H). 89 (S)-1-(2,4-Difluoro-MS(APCI)M+1=362.2 phenyl)-4-fluoro-3- ¹H NMR(400MHz, DMSO-D6) δppm1.4(m, 1H), 1.6(m, 1H), (piperidin-3- 1.8(m, 2H), 2.3(m, 1H), 2.8(t,J=12.1Hz, 2H), 3.2(m, 1H), ylmethoxy)-1H- 3.4(m, 1H), 4.3(dd, J=10.5,7.3Hz, 1H), 4.3(m, 1H), 7.0(dd, indazole J=10.6, 7.4Hz, 1H), 7.1(dd,J=8.4, 2.8Hz, 1H), 7.3(m, 1H), hydrochloride 7.4(td, J=8.2, 5.1Hz, 1H),7.6(m, 1H), 7.7(td, J=8.9, 5.9Hz, 1H), 8.5(s, 1H). 90 1-(2,5-Difluoro-MS(APCI)M+1=348.2 phenyl)-4-fluoro-3- ¹H NMR(400MHz, DMSO-D6) δppm2.0(m, 2H), 2.3(m, 2H), (piperidin-4-yloxy)- 3.1(m, 2H), 3.2(m, 2H),5.1(m, 1H), 7.0(dd, J=10.5, 7.6Hz, 1H), 1H-indazole 7.2(dd, J=8.4,3.5Hz, 1H), 7.4(m, 1H), 7.5(td, J=8.2, 5.1Hz, hydrochloride 1H), 7.6(m,2H), 8.6(s, 1H). 91 (S)-1-(2,5-Difluoro- MS(APCI)M+1=362.2phenyl)-4-fluoro-3- ¹H NMR(400MHz, DMSO-D6) δppm 1.3(m, 1H), 1.6(m, 1H),(piperidin-3- 1.8(m, 2H), 2.3(m, 1H), 2.7(t, J=11.7Hz, 2H), 3.2(m, 1H),ylmethoxy)-1H- 3.4(m, 1H), 4.3(m, 2H), 7.0(dd, J=10.5, 7.6Hz, 1H),7.1(dd, indazole J=8.5, 3.4Hz, 1H), 7.4(m, 1H), 7.4(td, J=8.2, 5.1Hz,1H), hydrochloride 7.5(m, 2H), 8.5(s, 1H). 92 (R)-1-(2,4-Difluoro-MS(APCI)M+1=348.2 phenyl)-4-fluoro-3- ¹H NMR(400MHz, DMSO-D6) δppm1.8(m, 1H), 2.1(m, 1H), (pyrrolidin-3- 2.8(ddd, J=14.5, 7.2, 7.1Hz, 1H),3.0(dd, J=11.7, 7.1Hz, 1H), ylmethoxy)-1H- 3.2(m, 1H), 3.2(m, 2H),4.4(ddd, J=17.6, 10.4, 7.0Hz, 2H), indazole 6.9(dd, J=10.4, 7.7Hz, 1H),7.1(dd, J=8.5, 2.7Hz, 1H), 7.3(m, 1H), hydrochloride 7.4(td, J=8.2,5.1Hz, 1H), 7.6(ddd, J=11.1, 8.8, 2.8Hz, 1H), 7.7(td, J=8.9, 6.1Hz, 1H),9.2(s, 1H). 93 (R)-1-(2,5-Difluoro- MS(APCI)M+1=348.2phenyl)-4-fluoro-3- ¹H NMR(400MHz, DMSO-D6) δppm 1.8(m, 1H), 2.1(m, 1H),(pyrrolidin-3- 2.9(m, 1H), 3.0(dd, J=11.6, 7.2Hz, 1H), 3.2(m, 1H),3.3(m, 2H), ylmethoxy)-1H- 4.4(ddd, J=17.2, 10.3, 7.0Hz, 2H), 7.0(dd,J=10.5, 7.8Hz, 1H), indazole 7.1(dd, J=8.5, 3.7Hz, 1H), 7.4(m, 1H),7.5(td, J=8.2, 5.1Hz, hydrochloride 1H), 7.6(m, 2H), 9.2(s, 1H). 94(S)-1-(2,4-Difluoro- 172-174° C. phenyl)-4-fluoro-3- Found forC₁₈H₁₆F₃N₃O₂•1.0 HCl; C, 53.94; H, 4.08; N, 10.31; (morpholin-2- F,14.03; Cl, 8.76 ylmethoxy)-1H- [α]_(D) ²⁴=+1.8 degrees(MeOH, c=8.4)indazole hydrochloride 95 (S)-1-(2,5-Difluoro- 190-192° C.phenyl)-4-fluoro-3- Found for C₁₈H₁₆F₃N₃O₂•1.0 HCl: C, 54.04; H, 3.98;N, 10.31; (morpholin-2- F, 14.08; Cl, 8.84 ylmethoxy)-1H- [α]_(D)²⁴=+3.7 degrees(MeOH, c=8.4) indazole hydrochloride 96(±)-1-(3,4-Difluoro- MS(APCI)M+1=362.2 phenyl)-5-fluoro-3- Found forC₁₉H₁₈F₃N₃O1•1.0 HCl; C, 57.19; H, 4.79; N, 10.42; (piperidin-3- F,13.95; Cl, 8.95 ylmethoxy)-1H- ¹H NMR(400MHz, CD3CN) δppm 1.5(m, 1H),1.7(m, 1H), indazole 1.9(m, 2H), 2.4(m, 1H), 2.9(m, 2H), 3.3(m, 1H),3.5(m, 1H), hydrochloride 4.3(m, 1H), 4.4(m, 1H), 7.3(td, J=9.2, 2.6Hz,1H), 7.4(m, 3H), 7.6(m, 1H), 7.7(dd, J=9.3, 3.9Hz, 1H). 971-(3,4-Difluoro- MS(APCI)M+1=348.1 phenyl)-5-fluoro-3- Found forC₁₈H₁₆F₃N₃O1•1.1 HCl•0.35 H₂O; C, 54.58; H, 4.17; (piperidin-4-yloxy)-N, 10.51; F, 14.08; Cl, 9.15 1H-indazole ¹H NMR(400MHz, DMSO-D6) δppm2.1(m, 2H), 2.3(m, 2H), hydrochloride 3.1(m, 2H), 3.3(m, 2H), 5.2(m,1H), 7.4(td, J=9.2, 2.4Hz, 1H), 7.6(m, 3H), 7.8(m, 1H), 7.9(dd, J=9.0,3.9Hz, 1H), 9.0(bs, 2H). 98 (S)-(+)-4-Fluoro-1- 139-140° C.(2-fluorophenyl)-3- Found for C₁₈H₁₇F₂N₃O₂•C₄H₄O₄: C, 57.54; H, 4.51; N,9.04; (morpholin-2- F, 8.60 ylmethoxy)-1H- [α]_(D) ²⁴=+3.2 degrees(MeOH,c=7.6) indazole maleate 99 5-Fluoro-3- MS(APCI)M+1=327.2 (piperidin-3-¹H NMR(400MHz, DMSO-D6) δppm 1.4(m, 1H), 1.7(m, 1H), ylmethoxy)-1-1.9(m, 2H), 2.4(m, 1H), 2.8(m, 2H), 3.2(m, 1H), 3.4(m, 1H),pyridin-2-yl-1H- 4.3(dd, J=10.5, 7.1Hz, 1H), 4.4(m, 1H), 7.2(ddd, J=6.7,5.6, indazole 1.0Hz, 1H), 7.5(td, J=9.2, 2.6Hz, 1H), 7.6(dd, J=8.2,2.6Hz, 1H), hydrochloride 7.8(d, J=8.3Hz, 1H), 7.9(m, 1H), 8.5(m, 1H),8.7(dd, J=9.2, 4.5Hz, 1H), 8.8(m, 1H), 9.0(m, 1H). 1004-Fluoro-1-(2-fluoro- MS(APCI)M+1=330.1 phenyl)-3-(piperidin- ¹HNMR(400MHz, DMSO-D6) δppm 2.0(m, 2H), 2.3(d, 4-yloxy)-1H-indazoleJ=13.7Hz, 2H), 3.1(ddd, J=12.8, 8.7, 3.7Hz, 2H), 3.2(m, 2H),hydrochloride 5.1(dt, J=7.9, 4.0Hz, 1H), 6.9(dd, J=10.5, 7.8Hz, 1H),7.1(dd, J=8.4, 3.1Hz, 1H), 7.4(m, 2H), 7.5(m, 2H), 7.6(m, 1H), 8.9(s,2H) 101 5-Chloro-1-phenyl- MS(APCI)M+1=328.1 3-(piperidin-4-yloxy)- ¹HNMR(400MHz, DMSO-D6) δppm 2.1(m, 2H), 2.2(m, 2H), 1H-indazole 3.1(m,2H), 3.3(m, 2H), 5.1(dt, J=7.1, 3.5Hz, 1H), 7.3(t, J=7.3Hz,hydrochloride 1H), 7.5(m, 3H), 7.7(m, 2H), 7.8(d, J=9.0Hz, 1H), 7.9(d,J=1.5Hz, 1H), 8.9(s, 2H) 102 5-Chloro-1-(2-fluoro- MS(APCI)M+1=346.1phenyl)-3-(piperidin- ¹H NMR(400MHz, DMSO-D6) δppm 2.0(m, 2H), 2.2(m,2H), 4-yloxy)-1H-indazole 3.1(ddd, J=12.4, 8.0, 3.8Hz, 2H), 3.3(dd,J=8.1, 3.9Hz, 2H), hydrochloride 5.1(m, 1H), 7.3(dd, J=9.0, 3.4Hz, 1H),7.4(ddd, J=8.3, 5.3, 3.3Hz, 1H), 7.5(m, 3H), 7.6(t, J=7.8Hz, 1H), 7.9(d,J=2.2Hz, 1H), 9.0(s, 2H) 103 4-Fluoro-1-phenyl-3- MS(APCI)M+1=312.1(piperidin-4-yloxy)- ¹H NMR(400MHz, DMSO-D6) δppm 2.1(m, 2H), 2.3(m,2H), 1H-indazole 3.1(ddd, J=12.7, 8.7, 3.5Hz, 2H), 3.2(m, 2H), 5.1(ddd,J=7.4, hydrochloride 4.2, 3.8Hz, 1H), 6.9(dd, J=10.5, 7.8Hz, 1H), 7.3(t,J=7.4Hz, 1H), 7.4(td, J=8.2, 5.1Hz, 1H), 7.5(m, 3H), 7.7(m, 2H), 8.9(s,2H) 104 (S)-(−)-1-Phenyl-3- MS(APCI)M+1=309 (piperidin-3- 247-249° C.ylmethoxy)-1H- Found for C₁₈H₂₀N₄O•HCl: C, 62.41; H, 5.96; N, 16.01; Cl,10.50 pyrazolo[3,4- [α]_(D) ²⁴=−14.3 degrees(MeOH, c=5.3) b]pyridinehydrochloride 105 (S)-(+)-3-(Morpholin- MS(APCI)M+1=311 2-ylmethoxy)-1-109-115° C.(dec) phenyl-1H- Found for C₁₇H₁₈N₄O₂•HCl•0.25H₂O: C, 58.07;H, 5.52; N, pyrazolo[3,4- 15.86; Cl, 10.06 b]pyridine [α]_(D) ²⁴=+5.7degrees(MeOH, c=7.2) hydrochloride 106 1-(2-Fluorophenyl)-MS(APCI)M+1=150, 311 3-(piperidin-4-yloxy)- ¹H NMR(DMSO) δppm 7.7(d,1H), 7.6(t, 1H), 7.47.5(m, 3H), 1H-indazole L- 7.3-7.4(m, 1H), 7.25(m,1H), 7.2(t, 1H), 5.1(m, 1H), 3.3(m, 2H), tartrate 3.1(m, 2H), 2.2(m,2H), 2.0(m, 2H). 107 (S)-5-Fluoro-1-(2- MS(APCI)M+1=344 fluorophenyl)-3-181-182° C. (piperidin-3- ylmethoxy)-1H- indazole L-tartrate 1081-(2,6-Difluoro- MS(APCI)M+1=348.2 phenyl)-5-fluoro-3- ¹H NMR(400MHz,DMSO-D6) δppm 2.0(m, 2H), 2.2(m, 2H), (piperidin-4-yloxy)- 3.1(m, 2H),3.3(m, 2H), 5.1(m, 1H), 7.3(dd, J=9.0, 3.7Hz, 1H), 1H-indazole 7.4(m,3H), 7.6(m, 2H), 8.9(bs, 2H). hydrochloride 109 1-(2,6-Difluoro-MS(APCI)M+1=348.2 phenyl)-4-fluoro-3- ¹H NMR(400MHz, DMSO-D6) δppm2.0(m, 2H), 2.3(m, 2H), (piperidin-4-yloxy)- 3.1(m, 2H), 3.2(m, 2H),5.1(m, 1H), 7.0(dd, J=10.4, 7.7Hz, 1H), 1H-indazole 7.5(td, J=8.2,5.1Hz, 1H), 7.6(m, 3H), 7.8(ddd, J=11.8, 7.2, hydrochloride 2.2Hz, 1H),8.9(s, 1H). 110 (S)-1-(2,6-Difluoro- MS(APCI)M+1=362.2phenyl)-4-fluoro-3- ¹H NMR(400MHz, DMSO-D6) δppm 1.3(m, 1H), 1.7(m, 1H),(piperidin-3- 1.8(m, 2H), 2.4(m, 1H), 2.8(t, J=12.0Hz, 2H), 3.2(m, 1H),ylmethoxy)-1H- 3.4(m, 1H), 4.3(m, 2H), 7.0(dd, J=10.3, 7.6Hz, 1H),7.5(m, 1H), indazole 7.6(m, 3H), 7.8(ddd, J=11.8, 7.1, 2.1Hz, 1H),8.8(s, 1H). hydrochloride 111 (S)-1-(2,6-Difluoro- MS(APCI)M+1=362.2phenyl)-5-fluoro-3- ¹H NMR(400MHz, DMSO-D6) δppm 1.4(m, 1H), 1.7(m, 1H),(piperidin-3- 1.9(m, 2H), 2.3(m, 1H), 2.8(m, 2H), 3.2(d, J=12.9Hz, 1H),ylmethoxy)-1H- 3.4(dd, J=12.6, 3.0Hz, 1H), 4.3(m, 2H), 7.3(dd, J=9.2,3.8Hz, indazole 1H), 7.4(m, 3H), 7.6(m, 2H), 9.0(bs, 2H). hydrochloride

Example 112 1-(2-Fluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazole,L-tartrate A. Preparation of4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester

A stirred solution of 250 g (1.24 mole) of4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester in 2.3 L ofdichloromethane was cooled to −10° C. 188 g (1.86 mole) of triethylaminewas added in a narrow stream over a 20 minute period. There was nosignificant temperature change. The resulting solution was stirred at−10° C. for 30 minutes and then 172 g (1.50 mole) of methanesulfonylchloride was added dropwise over a 30 minute period. The temperaturerose to 0° C. during the addition. The resulting suspension was stirredat temperatures reaching 21° C. over the next 18 hours. The mixture wasfiltered and the solid was washed with 800 mL of ethyl acetate. Thewashing was added to the filtrate which was concentrated byapproximately 2 L. The residual suspension was diluted with 1 L of ethylacetate and filtered. The solid was washed with 500 mL of ethyl acetate.The washing was added to the filtrate which was passed through a silicagel (230-400 mesh) pad containing 350 g of adsorbent. The pad was washedwith 600 mL of ethyl acetate. The washing was added to the filtratewhich was concentrated to approximately 800 mL and diluted with 400 mLof hexane. The suspension was stirred at −10° C. for 2 hours andfiltered. The solid was rinsed with ethyl acetate:hexane (2: 1, 300 mL)and pressed dry under suction. Further drying in vacuo at 32° C. for 19hours provided 307 g (89%) of product.

B. Preparation of 2-amino-benzoic acid N′-(2-fluoro-phenyl)-hydrazide

A stirred suspension of 845 g (5.03 mole) of 97%(2-fluoro-phenyl)-hydrazine, hydrochloride in 7.6 L of ethanol at 21-22°C. was added in a stream 563 g (5.57 mole) of triethylamine over a 20minute period. A whitish gas formed initially. The resulting darkmixture was stirred at 21° C. for 20 minutes and then 854 g (5.03 mole)of 96% 1H-benzo[d][1,3]oxazine-2,4-dione was added. The resultingmixture was heated up to reflux (78° C.) over the next 1 hour. Duringthis period, vigorous gas evolution was noted. Reflux was maintained for2 hours and then the suspension was stirred at room temperature for 16hours. The solid was collected by filtration, rinsed once with 150 mL ofethanol, then once with 150 mL of ethanol: ethyl acetate (1:1), andpressed dry under suction. Further drying in vacuo at 35° C. for 7 hoursprovided 498 g (40%) of product. A second crop of 51 g (4%) of materialwas obtained from the mother liquor.

C. Preparation of 1-(2-fluoro-phenyl)-1H-indazol-3-ol

A stirred suspension of 105 g (0.429 mole) of 2-amino-benzoic acidN′-(2-fluoro-phenyl)-hydrazide in 1250 mL of ethanol and 1250 mL of 1Nhydrochloric acid was heated to 55° C. A solution of 59 g (0.858 mole)of sodium nitrite in 200 mL of water was added dropwise over a 30 minuteperiod. Approximately 10 minutes into the addition a solid beganseparating. External heating was continued until the reactiontemperature reached 65° C. and then it was turned off. The temperatureremained at 65-68° C. during the addition and gas evolution becamevigorous approximately halfway through the addition. Toward the end ofthe addition, gas evolution slowed and the temperature dropped below 65°C. External heating was reapplied and the mixture was stirred at 70° C.for 3 hours. The mixture was cooled to −10° C. and filtered. The solidwas rinsed once with 50 mL of ethanol, then once with 100 mL of water,and pressed dry under suction. Further drying in vacuo at 35° C. for 7hours afforded 92 g (94%) of product.

D. Preparation of4-[1-(2-Fluoro-phenyl)-1H-indazol-3-yloxy]-piperidine-1-carboxylic acidtert-butyl ester

To a stirred solution of 173 g (0.76 mole) of1-(2-fluoro-phenyl)-1H-indazol-3-ol in 1.5 L of N,N-dimethylformamide atroom temperature was added 371 g (1.14 mole) of cesium carbonate. Theresulting mixture was stirred at room temperature for 2 hours and then230 g (0.83 mole) of 4-methanesulfonyloxy-piperidine-1-carboxylic acidtert-butyl ester was added. The resulting mixture was stirred at 85-90°C. for 17 hours, cooled to room temperature, and then concentrated invacuo by approximately 1 L. The residue was quenched by the dropwiseaddition of 500 mL of saturated aqueous ammonium chloride. The resultingmixture was stirred at room temperature for 15 minutes and then pouredinto 2.5 L of stirred ice-water. The resulting mixture was extractedonce with 1.5 L dichloromethane and then twice with 0.75 L portions ofdichloromethane. Some emulsion formation occurred during theseextractions. The combined extracts were dried over magnesium sulfate andconcentrated in vacuo to an oil. A vacuum pump was used to removeremaining N,N-dimethylformamide. The residue was taken up in 1.2 L ofether. The mixture was stirred at room temperature for 10 minutes andfiltered. The insoluble solid was rinsed with ether and the rinsingadded to the filtrate. The solid was dried in vacuo at 30° C. for 6hours to afford 11.6 g of recovered 1-(2-fluoro-phenyl)-1H-indazol-3-ol.The filtrate was concentrated in vacuo to 268 g (86%) of the product asa viscous, red oil.

E. Preparation of 1-(2-Fluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazole,hydrochloride

To a stirred solution of 187 g (0.456 mole) of4-[1-(2-fluoro-phenyl)-1H-indazol-3-yloxy]-piperidine-1-carboxylic acidtert-butyl ester in 600 mL of ethyl acetate was added 300 mL of 4Mhydrogen chloride in dioxane dropwise over a 30 minute period. Thetemperature rose to 24° C. from 21° C. during the addition. When theaddition was complete, gas evolution was observed and the temperaturerose to 28° C. A cold water bath was used to lower the temperature to18° C. After stirring for approximately 40 min, a solid beganseparating. Stirring was continued at 18-20° C. for 3 hours and then at−10° C. (ice-acetone bath) for 1 hour. The solid was collected byfiltration, rinsed with 60 mL of ethyl acetate and pressed dry undersuction. Further drying in vacuo at 30° C. for 16 hours afforded 87.3 g(55%) of product. The combined filtrate and washing was concentrated invacuo to near dryness. The residue was taken up in 250 mL of ethylacetate and the suspension was stirred at −10° C. for 2 hours. The solidwas collected by filtration, rinsed with 30 mL of ethyl acetate andpressed dry under suction. Further drying in vacuo at 30° C. for 16hours provided an additional 23.2 g (15%) of product. Total yield=110.5g (70%). ¹H NMR (CD₃OD) δ ppm: 7.7 (d, 1H), 7.6 (t, 1H), 7.5-7.6 (m,2H), 7.3-7.5 (m, 2H), 7.25 (m, 1H), 7.2 (t, 1H), 5.2 (m, 1H), 3.4-3.5(m, 2H), 3.2-3.3 (m, 2H), 2.3-2.4 (m, 2H), 2.2-2.3 (m, 2H).

F. Preparation of 1-(2-Fluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazole,L-tartrate

A mixture of 276 g (0.794 mole of1-(2-fluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazole, hydrochloride in525 mL of tetrahydrofuran and 3.0 L of water was stirred until most(>98%) of the solid dissolved. The solution was filtered from the smallamount of insoluble material. To the stirred filtrate was added 135 g(1.28 mole) of sodium carbonate slowly. The resulting mixture wasstirred vigorously for 5 minutes and then was extracted twice with 2 Lof ether and then once with 1 L of ether. The combined extracts weredried over magnesium sulfate and concentrated in vacuo to dryness. Theresidual viscous oil (236 g, 96%) was dissolved in 600 mL oftetrahydrofuran. A solution of L-tartaric acid in 2.4 L of water wasadded to the stirred tetrahydrofuran solution. The resulting solutionwas concentrated in vacuo to remove the tetrahydrofuran as a solidseparated. The resulting suspension was stirred at 5° C. for 1 hour andfiltered. The solid was rinsed once with 30 mL of tetrahydrofuran, thenonce with 100 mL of water, and pressed dry under suction. Further dryingin vacuo at 35° C. for 16 hours afforded 234.8 g (67%) of product. Asecond crop of 35.5 g (10%) was obtained from the mother liquor. Totalyield=270.3 g (77%). ¹H NMR (DMSO) δ ppm: 7.7 (d,1H), 7.6 (t, 1H),7.4-7.5 (m, 3H), 7.3-7.4 (m, 1H), 7.25 (m, 1H), 7.2 (t, 1H), 5.1 (m,1H), 3.3 (m, 2H), 3.1 (m, 2H), 2.2 (m, 2H), 2.0 (m, 2H).

Example 113 Synthesis of Salts of1-(2-fluorophenyl)-3-(piperidin-4yloxy)-1H-indazole A.1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-tartrate

65.9 mg of L-tartaric acid was added to 136.68 mg of1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole (clear oil) in12.45 ml of methanol. The mixture was place under a stream of N₂ gasuntil only approximately 1 ml of solution remained. Precipitation of thesalt was observed during this step. Approximately 5 ml of acetone wasadded and the subsequent solution was then stirred briefly (˜2 min). Awhite solid was recovered using vacuum filtration with a membranefilter. The solid was dried in a vacuum dessicator at ambienttemperature (pressure not controlled).

B. 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole edisylate

3.145 mg of ethanedisulfonic acid was added to 0.56 ml of a solution of1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole in MeOH (methanol)(concentration=10.3 mg/ml). The solution was heated and stirred inuncapped vials and then placed under a stream of N₂ gas. These stepswere repeated until approximately 0.100 ml or less of solution remained.Approximately 0.500 ml of MTBE (methyl tert-butyl ether) was then added.Precipitation was observed and the suspension was capped and stirred for3 hours or less. The vial was then uncapped and allowed to stir forapproximately 16 hours. A dry white solid remained.

C. 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole fumarate

2.162 mg of fumaric acid was added to 0.58 ml of a solution of1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole in MeOH(concentration=10.3 mg/ml). The solution was heated and stirred inuncapped vials and then placed under a stream of N₂ gas. These stepswere repeated until approximately 0.100 ml or less of solution remained.Approximately 0.500 ml of MTBE was then added. Precipitation wasobserved and the suspension was capped and stirred for 3 hours or less.The vial was then uncapped and allowed to stir for approximately 16hours. A dry white solid remained.

D. 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole hydrobromide

4.840 mg of concentrated hydrobromic acid was added to 0.89 ml of asolution of 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole in MeOH(concentration=10.3 mg/ml). The solution was placed under a stream of N₂gas until no solvent remained. Approximately 0.5 ml of MTBE was addedand the sample was left open and stirred overnight. A white solidremained upon recovery.

E. 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole hemi L-tartrate

9.94 mg of L-tartaric acid was added to 4 ml of a solution of1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole in MeOH(concentration=10.3 mg/ml). The solution was placed under a stream of N₂gas until approximately 0.2 ml of solution was left. Approximately 0.75ml of IPA (isopropyl alcohol) was then added and solution was returnedto aforementioned gas stream for less than 1 minute. Precipitation wasobserved and the suspension was capped. The suspension was stirredovernight, and the solution had become a gel. Approximately 3 ml ofacetone was added and precipitation was observed. A solid was recoveredon a membrane filter using vacuum filtration.

F. 1-(2-fluorophenyl)-3-(piperidin-4yloxy)-1H-indazole L-malate

2.383 mg of L-malic acid was added to 0.55 ml of a solution of1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole in MeOH(concentration=10.3 mg/ml). The solution was heated and stirred inuncapped vials and then placed under a stream of N₂ gas. These stepswere repeated until approximately 0.100 ml or less of solution remained.Approximately 0.500 ml of MTBE was then added. Precipitation wasobserved and the suspension was capped and stirred for 3 hours or less.Spheres of gel were observed and no solid was seen. The vial was thenuncapped and allowed to stir for approximately 16 hours. A dry whitesolid remained. Subsequent attempts at repeating this procedure on alarger scale did not generate solid material.

G. 1-(2-fluorophenyl)-3-(piperidin-4yloxy)-1H-indazole phosphate

2.09 mg of concentrated phosphoric acid was added to 0.58 ml of asolution of 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole in MeOH(concentration=10.3 mg/ml). The solution was heated and stirred inuncapped vials and then placed under a stream of N₂ gas. These stepswere repeated until approximately 0.100 ml or less of solution remained.Approximately 0.500 ml of MTBE was then added. Precipitation wasobserved and the suspension was capped and stirred for 3 hours or less.The vial was then uncapped and allowed to stir for approximately 16hours. A dry white solid remained.

H. 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole sulfate

1.9 mg of concentrated sulfuric acid was added to 0.58 ml of a solutionof 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole in MeOH(concentration=10.3 mg/ml). The solution was heated and stirred inuncapped vials and then placed under a stream of N₂ gas. These stepswere repeated until approximately 0.100 ml or less of solution remained.Approximately 0.500 ml of MTBE was then added. Precipitation wasobserved and the suspension was capped and stirred for 3 hours or less.The vial was then uncapped and allowed to stir for approximately 16hours. A dry white solid remained.

I.

Citric acid, benzene acid, camphorsulfonic acid, and methane sulfonicacid aliquots were added to equimolar aliquots of1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole similarly to theaforementioned methods. Solids were not generated using theseconditions.

Example 114 Powder X-ray Diffraction (PXRD)

The experimental powder x-ray diffraction spectra of several1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole salts from Example114 were determined out utilizing a Bruker D8 X-ray powderdiffractometer with GADDS (General Area Diffraction Detector System) C2system with a single Goebel mirror configuration. The scans were runwith the detector at 15.0 cm. Theta 1, or the collimator, was at 7° andTheta 2, or the detector, was at 17°. The scan axis was 2-omega with awidth of 3°. At the end of each scan theta 1 is at 10° and theta 2 is at14°. Samples were run for 60 seconds at 40 kV and 40 mA with CuKα(λ=1.5419 Å) radiation. Scans were integrated from 6.4° to 41° 2 q. Thesamples were run in ASC-6 sample holders purchased from Gem Dugout(State College, PA). The samples were placed in the cavity in the middleof the sample holder, and flattened with a spatula to be even with thesurface of the holder. All analyses were conducted at room temperature(generally 20° C.-30° C.). Scan was evaluated using DiffracPlussoftware, release 2003, with Eva version 9.0.0.2. The PXRD spectra arereported in FIGS. 1-8:1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-tartrate (FIG.1); 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole edisylate (FIG.2); 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole fumarate (FIG.3); 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole hydrobromide(FIG. 4); 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazolehemi-L-tartrate (FIG. 5);1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-malate (FIG. 6);1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole phosphate (FIG. 7);and 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole sulfate (FIG.8).

Summaries of the angle (2theta) values and intensity values (as a % ofthe value of the tallest peak) are reported in Tables 1-8 below.

TABLE 1 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-tartrateAngle (2theta) Intensity % 37.8° 16.7 33.8° 17.5 16.8° 17.5 11.9° 17.613.2° 18.5 29.0° 18.9 19.5° 20.9 27.6° 21 31.9° 21.1 25.5° 21.7 17.9°22.2 23.8° 22.6 20.1° 23.4 26.0° 27.6 23.2° 28.6 29.6° 30 21.4° 30.522.0° 37.3 20.9° 49.4 18.6° 100

TABLE 2 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole edisylateAngle (2theta) Intensity % 33.0° 26.8 15.7° 27.3 12.4° 27.4 14.1° 34.128.2° 35 30.1° 39 17.3° 46.4 27.1° 46.7 19.0° 56.2 25.5° 57.9 24.1° 58.211.6° 79.5 22.5° 94.8 20.0° 97.5 21.2° 100

TABLE 3 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole fumarateAngle (2theta) Intensity % 12.7° 22 31.5° 24.6 11.7° 25.3 27.8° 29.622.4° 31 26.6° 31 20.9° 35.1 17.2° 36.1 15.9° 36.3 29.5° 45.8 28.4° 50.425.3° 52.2 18.1° 67.9 24.6° 70.6 20.1° 85.8 23.2° 100

TABLE 4 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazolehydrobromide Angle (2theta) Intensity % 18.0° 20.5 21.6° 20.5 38.0° 22.215.4° 23.8 14.1° 25 30.4° 25.8 26.3° 28.1 33.5° 32 28.0° 34.9 25.6° 37.912.6° 38.1 29.3° 44.3 20.1° 57.7 24.0° 67.9 23.8° 70.3 16.8° 71.2 25.1°92.7 20.9° 100

TABLE 5 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazolehemi-L-tartrate Angle (2theta) Intensity % 10.3° 24.9 14.9° 51.3 15.7°10.2 17.0° 23.8 19.0° 100 20.5° 20.3 21.6° 58.9 22.7° 20.7 23.9° 32.724.7° 15.7 25.6° 14.4 27.7° 8.6 29.8° 16.7 32.6° 9.9 34.5° 15.2 36.2°12.5 39.2° 8.7

TABLE 6 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-malateAngle (2theta) Intensity % 36.8° 16.9 24.5° 17.7 26.3° 20.7 28.7° 20.812.2° 21.5 25.2° 22.3 23.1° 23 18.2° 24.5 30.4° 25.1 27.3° 28.9 14.7°34.7 20.9° 34.8 11.4° 36.1 19.2° 39.9 16.7° 50.1 21.9° 51.3 21.5° 51.520.1° 100

TABLE 7 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole phosphateAngle (2theta) Intensity % 12.1° 20.2 34.7° 20.3 14.0° 20.7 30.9° 2125.6° 22.2 29.3° 23.5 33.4° 28 16.9° 32.1 20.6° 34.6 15.6° 34.9 26.9°43.1 22.8° 46.5 20.0° 48.1 27.3° 49.3 17.9° 56.3 21.2° 72.5 24.3° 74.223.2° 100

TABLE 8 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole sulfateAngle (2theta) Intensity % 26.7° 14.8 27.6° 16 17.2° 19.3 21.4° 20.625.4° 21.5 29.7° 24.4 16.4° 27.9 15.0° 32.6 20.0° 35.7 18.3° 37.9 23.0°44.1 24.3° 44.5 20.2° 49.8 12.1° 100

Example 115 Differential Scanning Calorimetry (DSC)

Differential Scanning Calorimetry (DSC) was carried out on theL-tartrate, edisylate, fumarate, hydrobromide, hemi L-tartrate,L-malate, phosphate, and the sulfate salts of1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole of Example 113 on aTA Instruments DSC Q1000 V8.1 Build 261 (TA Instruments, New Castle,Del.). Samples were prepared by weighing 2-4 mg of sample into analuminum pan which was then covered with a pierced aluminum lid (TAInstruments' part nos. 900786.901 (bottoms) and 900779.901 (top)). Datawas analyzed using Universal Analysis 2000 for Windows95/98/2000/NT/Me/XP version 3.8B, Build 3.8.019.

The rate of temperature increase for all experiments was the same forall samples except for the L-tartrate salt. The experiments started atambient temperature and heated the sample at 20° C./minute under anitrogen gas purge (flow rate was 50 ml/min). The L-tartrate salt washeated at 10° C./minute.

The edisylate, hydrobromide, hemi L-tartrate, and sulfate salts wereheated to 350° C. The fumarate, L-malate, and phosphate salts wereheated to 250° C. The L-tartrate salt was heated to 300° C. The meltingpoint onset (° C.) for the salts are reported in Table 9:

TABLE 9 Melting Peak Onset Name (° C.)1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L- 199.98° C.tartrate 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazoleInconclusive edisylate1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole 185.68° C. fumarate1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole 134.46° C.hydrobromide 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole hemi178.74° C. L-tartrate1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L- 145.55° C.malate 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole 192.97° C.phosphate 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazoleInconclusive sulfate

Example 116 Single Crystal X-ray Data and Calculated PXRD for1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-tartrate

The single crystal structure of1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole L-tartrate wassolved from material synthesized as described above in Example 113. Thedata were collected at room temperature using an APEX (Bruker-AXS)diffractometer. The structure was solved in the orthorhombic space groupP2₁ with Z=4 (a=9.585(3)) Å, b=14.978(5)) Å, c=14.952(5)) Å. Thestructure solution contains two free-form L-tartrate counterion pairs inthe asymmetric unit. Hydrogen atoms located on hetero-atoms were foundexperimentally, the remaining hydrogen atoms were placed in calculatedpositions. The crystal structure shows that there is one L-tartratecounter ion per 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole.

The crystal structure (not shown) is consistent with the molecularformula of 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazoleL-tartrate. The final model was refined to a goodness fit of 1.009 withR₁=0.0481 (I>2sigma(I)) and wR₂=0.0863 (I>2sigma(I)). Thestereochemistry of 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazolewas determined from the known stereochemistry of the L-tartratecounterion. A calculated PXRD pattern was obtained from Material Studiossoftware suite (FIG. 16) using a Reitveld refinement. A summary of theangle (2theta) values and intensity values (as a % of the value of thetallest peak) from the calculated spectrum is reported below in Table10.

TABLE 10 Angle (2Theta) Intensity % 20.1° 16.0 21.2° 16.5 29.7° 17.121.4° 19.2 17.9° 20.0 22.1° 20.7 20.7° 21.1 23.4° 21.3 20.9° 31.9 13.2°32.7 11.8° 66.1 18.7° 100.0

BIOLOGICAL EXAMPLE 1

hNET Receptor Binding:

Cell pastes of HEK-293 cells transfected with a human norepinephrinetransporter cDNA were prepared. The cell pastes were resuspended in 400to 700 ml of Krebs-HEPES assay buffer (25 mM HEPES, 122 mM NaCl, 3 mMKCl, 1.2 mM MgSO₄, 1.3 mM CaCl₂, and 11 mM glucose, pH 7.4) with aPolytron homogenizer at setting 7 for 30 seconds. Aliquots of membranes(5 mg/ml protein) were stored in liquid nitrogen until used.

The binding assay was set up in Beckman deep-well polypropylene plateswith a total volume of 250 μl containing: test compound (10⁻⁵M to10⁻¹²M), cell membranes, and 50 pM [¹²⁵I]-RTI-55 (Perkin Elmer, NEX-272;specific activity 2200 Ci/mmol). The reaction was incubated by gentleagitation for 90 minutes at room temperature and was terminated byfiltration through Whatman GF/C filter plates using a Brandel 96-wellplate harvester. Scintillation fluid (100 μl) was added to each well,and bound [¹²⁵I]-RTI-55 was determined using a Wallac Trilux Beta PlateCounter. Test compounds were run in duplicate, and specific binding wasdefined as the difference between binding in the presence and absence of10 μM desipramine.

Excel and GraphPad Prism software were used for data calculation andanalysis. IC₅₀ values were converted to K_(i) values using theCheng-Prusoff equation. The K_(i) values (nM) for the hNET are reportedbelow in Table 11.

hSERT Receptor Binding

Cell pastes of HEK-293 cells transfected with a human serotonintransporter cDNA were prepared. The cell pastes were resuspended in 400to 700 ml of Krebs-HEPES assay buffer (25 mM HEPES, 122 mM NaCl, 3 mMKCl, 1.2 mM MgSO₄, 1.3 mM CaCl₂, and 11 mM glucose, pH 7.4) with aPolytron homogenizer at Setting 7 for 30 seconds. Aliquots of membranes(˜2.5 mg/ml protein) were stored in liquid nitrogen until used.

Assays were set up in FlashPlates pre-coated with 0.1% PEI in a totalvolume of 250 μl containing: test compound (10⁻⁵M to 10⁻¹²M), cellmembranes, and 50 pM [¹²⁵I]-RTI-55 (Perkin Elmer, NEX-272; specificactivity 2200 Ci/mmol). The reaction was incubated and gently agitatedfor 90 minutes at room temperature, and terminated by removal of assayvolume. Plates were covered, and bound [¹²⁵I]-RTI-55 was determinedusing a Wallac Trilux Beta Plate Counter. Test compounds were run induplicate, and specific binding was defined as the difference betweenbinding in the presence and absence of 10 μM citalopram.

Excel and GraphPad Prism software were used for data calculation andanalysis. IC₅₀ values were converted to K_(i) values using theCheng-Prusoff equation. The K_(i) values (nM) for the hSERT are reportedbelow in Table 11:

TABLE 11 SERT Ex. # NET K_(i) K_(i) 1 3.14 51.11 2 9.28 1622.00 3 3.40831.50 4 3.00 270.33 5 84.00 1607.00 6 1.65 191.50 7 5.30 54.72 8 5.1939.03 9 5.63 81.57 10 14.30 36.09 11 13.96 279.00 12 12.50 1010.00 13131.00 5289.00 14 13.05 100.37 15 329.00 1458.50 16 21.50 224.00 17150.50 28.00 18 95.50 121.00 19 5.43 486.00 20 20.17 122.32 21 12.501120.50 22 25.69 68.22 23 11.48 1526.75 24 9.65 5427.33 25 3.20 670.5026 6.90 346.00 27 6.34 42.29 28 5.10 640.00 29 4055.00 342.30 30 4.4464.64 31 6.58 133.50 32 3.41 33.56 33 19.16 197.90 34 30.02 80.95 3524.04 82.60 36 5.16 82.72 37 6.05 104.80 38 6.09 199.40 39 9.57 34.35 405.02 30.75 41 299.00 79.66 42 25.86 80.99 43 17.92 137.60 44 100.00365.00 45 3.20 47.50 46 5.70 413.00 47 13.00 47.00 48 10.20 297.50 4998.50 20.50 50 5.20 1141.50 51 11.86 53.74 52 35.69 45.35 53 54.09145.70 54 274.10 28.46 55 71.17 125.60 56 6.13 9.99 57 18.13 52.19 5855.98 133.60 59 69.14 32.72 60 221.00 76.75 61 20.43 21.67 62 495.00313.80 63 39.54 19.42 64 512.40 271.90 65 4327.00 81.22 66 16.93 120.5067 19.72 190.50 68 219.50 359.30 69 98.03 339.40 70 33.58 199.50 7195.50 20.51 72 27.38 9.76 73 29.34 303.80 74 60.50 791.70 75 36.39 39.7776 40.36 157.80 77 24.81 49.55 78 10.16 39.92 79 32.81 23.72 80 15.0423.88 81 49.80 448.70 82 23.23 635.40 83 49.26 191.40 84 38.13 486.80 8512.50 1007.00 86 113.90 100.90 87 197.30 56.98 88 16.26 88.08 89 22.43402.80 90 10.16 142.10 91 7.88 610.20 92 28.47 126.30 93 16.35 224.50 9440.25 2848.75 95 5.47 3465.67 96 49.53 172.30 97 28.51 39.52 98 27.333856.50 99 319.20 258.70 100 4.63 101.50 101 607.00 304.00 102 71.54129.30 103 34.15 292.80 104 89.00 1579.50 105 294.25 4239.75 106 107 1085.72 42.97 109 46.17 279.00 110 16.33 422.50

BIOLOGICAL EXAMPLE 2

Compounds of the present invention may be assayed for their ability toalleviate capsaicin-induced mechanical allodynia in a rat model (e.g.,Sluka (2002) J of Neuroscience, 22(13): 5687-5693). For example, a ratmodel of capsaicin-induced mechanical allodynia was carried out asfollows:

On day 0, male Sprague-Dawley rats (˜150 g) in the dark cycle wereplaced in suspended wire-bottom cages and allowed to acclimate for 0.5hour in a darkened, quiet room. The day 0 paw withdrawal threshold (PWT)was determined on the left hind paw by Von Frey hair assessment usingthe Dixon up and down method. After assessment, the plantar muscle ofthe right hind paw was injected with 100 μl capsaicin (0.25% (w/v) in10% ethanol, 10% Tween 80, in sterile saline). On day 6 the PWT of theleft hindpaw (contralateral from injection site) was determined for eachanimal. Animals from the day 6 prereads with PWT≦11.7 g were consideredallodynic responders and were regrouped so that each cage had similarmean PWT values.

Subcutaneous Dosing:

On day 7, responders were dosed subcutaneously with 30 mg of thecompound of Example 7/kg body weight, 10 mg of the compound of thecompound of Example 48/kg body weight, or with vehicle alone. Thevehicle was phosphate buffered saline containing 2% Cremophor® EL(BASF).

Example 7 Dosed Animals:

For the animals dosed with the compound of Example 7, the contralateralPWT values were determined at 2 hour after the single dose, with theinvestigator blinded to the dosing scheme.

For each animal, the day 6 PWT value was subtracted from the 2 hour PWTvalue for the 10 mg/kg doses to give a delta PWT value that representsthe change in PWT due to the 1 hour drug treatment. In addition, the day6 PWT was subtracted from the day 0 PWT to give the baseline window ofallodynia present in each animal. To determine % inhibition of allodyniaof each animal normalized for vehicle controls, the following formulawas used: % Inhibition of Allodynia=100×[(Delta PWT(drug)−mean DeltaPWT(vehicle))/(Baseline−mean Delta PWT(vehicle))].

The mean percent inhibition of allodynia value (for eight animalsassayed) is shown in Table 12. Compounds exhibiting a greater than 30%inhbition in allodynia assay are considered active.

Example 48 Dosed Animals:

For the animals dosed with the compound of Example 48, the contralateralPWT values were determined at 1 hour after the single dose, with theinvestigator blinded to the dosing scheme.

For each animal, the day 6 PWT value was subtracted from the 1 hour PWTvalue for the 10 mg/kg doses to give a delta PWT value that representsthe change in PWT due to the 1 hour drug treatment. In addition, the day6 PWT was subtracted from the day 0 PWT to give the baseline window ofallodynia present in each animal. To determine % inhibition of allodyniaof each animal normalized for vehicle controls, the following formulawas used: % Inhibition of Allodynia=100×[(Delta PWT(drug)−mean DeltaPWT(vehicle))/(Baseline−mean Delta PWT(vehicle))].

The mean percent inhibition of allodynia value (for eight animalsassayed) is shown in Table 12 +/− the standard error of the mean (SEM).Compounds exhibiting a greater than 30% inhbition in allodynia assay areconsidered active.

TABLE 12 Dose (mg compound/ % Inhibition Ex. # kg body weight) ofAllodynia +/− SEM 7 30 mg/kg 71.5 +/− 4.6 48 10 mg/kg 74.9% +/− 14.8Oral Dosing:

On day 7, responders were dosed orally with 10 mg compound/kg bodyweight, or with vehicle alone. The vehicle was in phosphate bufferedsaline containing 0.5% HPMC (hydroxy-propylmethylcellulose) and 0.2%TWEEN™ 80. The test compounds were formulated in the vehicle foradministration. The contralateral PWT values were determined at 2 hoursafter the single dose, with the investigator blinded to the dosingscheme.

For each animal, the day 6 PWT value was subtracted from the 2 hour PWTvalue to give a delta PWT value that represents the change in PWT due tothe 2 hour drug treatment. In addition, the day 6 PWT was subtractedfrom the day 0 PWT to give the baseline window of allodynia present ineach animal. To determine % inhibition of allodynia of each animalnormalized for vehicle controls, the following formula was used: %Inhibition of Allodynia=100×[(Delta PWT(drug)−mean DeltaPWT(vehicle))/(Baseline−mean Delta PWT(vehicle))].

The mean percent inhibition of allodynia values (for eight animalsassayed for each compound) +/− the standard error of the mean (SEM) areshown in Table 13. Compounds exhibiting a greater than 30% inhbition inallodynia assay are considered active.

TABLE 13 Ex. # % inhibition +/− SEM 1 67.7 +/− 8.3 7 12.2 +/− 8.3 8 11.5+/− 9.0 9 34.1 +/− 8.7 14 30.8 +/− 9.7 20 27.5 +/− 10.4 20 41.1 +/− 9.120 27.3 +/− 6.3 27 27.0 +/− 3.0 30 68.0 +/− 13 30 67.7 +/− 13.5 31 47.0+/− 13.0 31 46.7 +/− 13.2 32 60.7 +/− 15.1 42 31.7 +/− 9.9 43 55.4 +/−16.7 45 46.2 +/− 10.7 51 26.0 +/− 7.0 56 11.0 +/− 10.0 57 26.0 +/− 23.057 25.7 +/− 22.8 100  8.7 +/− 9.2

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application and thescope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1. A compound(S)-1-(2,5-difluoro-phenyl)-5-fluoro-3-(morpholin-2-ylmethoxy)-1H-indazole,or a pharmaceutically acceptable salt thereof.
 2. A compound as in claim1, wherein the pharmaceutically acceptable salt of(S)-1-(2,5-difluoro-phenyl)-5-fluoro-3-(morpholin-2-ylmethoxy)-1H-indazoleis an acetate, aspartate, benzoate, benzenesulfonate,bicarbonate/carbonate, bisulfate, caprylate, camphor sulfonate,chlorobenzoate, citrate, 1,2-ethane disulfonate, dihydrogenphosphate,dinitrobenzoate, ethane sulfonate, fumarate, gluceptate, gluconate,glucoronate, hibenzate, hydrochloride/chloride, hydrobromide/bromide,hydroiodide/iodide, isobutyrate, monohydrogen phosphate, isethionate,D-lactate, L-lactate, malate, maleate, malonate, mandelate,methanesulfonate, metaphosphate, methylbenzoate, methylsulfate,2-naphthalene sulfonate, nicotinate, nitrate, orotate, oxalate,palmoate, phenylacetate, phosphate, phthalate, propionate,pyrophosphate, pyrosulfate, saccharate, sebacate, stearate, suberate,succinate sulfate, sulfite, D-tartrate, L-tartrate, toluene sulfonate,xinafoate, arginate, gluconate, or galacturonate salt.
 3. Apharmaceutical composition comprising: a therapeutically effectiveamount of the compound according to claim 2, or the pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.
 4. Apharmaceutical composition comprising: a therapeutically effectiveamount of the compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.
 5. Amethod of acutely or chronically treating attention deficithyperactivity disorder comprising administering to a mammal in need ofsuch treatment a therapeutically effective amount of the compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof. 6.A method of acutely or chronically treating a disorder or conditionselected from the group consisting of: neuropathic pain, stress urinaryincontinence, anxiety, depression, fibromyalgia, pain associated withfibromyalgia, pain associated with oseoarthritis, pain associated withrheumatoid arthritis, bipolar disorder, and schizophrenia comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of the compound according to claim 1, or apharmaceutically acceptable salt thereof.
 7. A method of claim 5 ofacutely or chronically treating attention deficit hyperactivity disordercomprising administering to a mammal in need of such treatment atherapeutically effective amount of a salt of(S)-1-(2,5-difluoro-phenyl)-5-fluoro-3-(morpholin-2-ylmethoxy)-1H-indazolewherein the salt is an acetate, aspartate, benzoate, benzenesulfonate,bicarbonate/carbonate, bisulfate, caprylate, camphor sulfonate,chlorobenzoate, citrate, 1,2-ethane disulfonate, dihydrogenphosphate,dinitrobenzoate, ethane sulfonate, fumarate, gluceptate, gluconate,glucoronate, hibenzate, hydrochloride/chloride, hydrobromide/bromide,hydroiodide/iodide, isobutyrate, monohydrogen phosphate, isethionate,D-lactate, L-lactate, malate, maleate, malonate, mandelate,methanesulfonate, metaphosphate, methylbenzoate, methylsulfate,2-naphthalene sulfonate, nicotinate, nitrate, orotate, oxalate,palmoate, phenylacetate, phosphate, phthalate, propionate,pyrophosphate, pyrosulfate, saceharate, sebacate, stearate, suberate,succinate sulfate, sulfite, D-tartrate, L-tartrate, toluene sulfonate,xinafoate, arginate, gluconate, or galacturonate salt.
 8. A method ofclaim 6 of acutely or chronically treating a disorder or conditionselected from the group consisting of: neuropathic pain, stress urinaryincontinence, anxiety, depression, fibromyalgia, pain associated withfibromyalgia, pain associated with osteoarthritis, pain associated withrheumatoid arthritis, bipolar disorder, Alzheimer's disease, andschizophrenia, the method comprising administering to a mammal in needof such treatment a therapeutically effective amount of a salt of(S)-1-(2,5-difluoro-phenyl)-5-fluoro-3-(morpholin-2-ylmethoxy)-1H-indazolewherein the salt is an acetate, aspartate, benzoate, benzenesulfonate,bicarbonate/carbonate, bisulfate, caprylate, camphor sulfonate,chlorobenzoate, citrate, 1,2-ethane disulfonate, dihydrogenphosphate,dinitrobenzoate, ethane sulfonate, fumarate, gluceptate, gluconate,glucoronate, hibenzate, hydrochloride/chloride, hydrobromide/bromide,hydroiodide/iodide, isobutyrate, monohydrogen phosphate, isethionate,D-lactate, L-lactate, malate, maleate, malonate, mandelate,methanesulfonate, metaphosphate, methylbenzoate, methylsulfate,2-naphthalene sulfonate, nicotinate, nitrate, orotate, oxalate,palmoate, phenylacetate, phosphate, phthalate, propionate,pyrophosphate, pyrosulfate, saccharate, sebacate, stearate, suberate,succinate sulfate, sulfite, D-tartrate, L-tartrate, toluene sulfonate,xinafoate, arginate, gluconate, or galacturonate salt.
 9. A compound ofclaim 1 which is(S)-1-(2,5-difluoro-phenyl)-5-fluoro-3-(morpholin-2-ylmethoxy)-1H-indazolemaleic acid salt.
 10. A pharmaceutical composition of claim 4 whereinthe compound of claim 1 is(S)-1-(2,5-difluoro-phenyl)-5-fluoro-3-(morpholin-2-ylmethoxy)-1H-indazolemaleic acid salt.
 11. The method according to claim 5, wherein thecompound of claim 1 is(S)-1-(2,5-difluoro-phenyl)-5-fluoro-3-(morpholin-2-ylmethoxy)-1H-indazolemaleic acid salt.
 12. The method according to claim 6, wherein thecompound of claim 1 is(S)-1-(2,5-difluoro-phenyl)-5-fluoro-3-(morpholin-2-ylmethoxy)-1H-indazolemaleic acid salt.